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Salmón-Gómez L, Catalán V, Ramírez B, Aguas-Ayesa M, Rodríguez A, Becerril S, Valentí V, Moncada R, Perdomo CM, Silva C, Escalada J, Frühbeck G, Gómez-Ambrosi J. Differential effects of bariatric surgery on circulating GDF15 and FGF21 levels: Implications for glycemic status and weight loss outcomes. Eur J Clin Invest 2025:e70069. [PMID: 40377893 DOI: 10.1111/eci.70069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 04/28/2025] [Indexed: 05/18/2025]
Abstract
BACKGROUND Type 2 diabetes (T2D) is a comorbidity commonly associated with obesity. Elevated concentrations of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) are associated with these conditions, making both cytokines interesting candidates to combat them. This study aimed to analyse the relationship between changes in plasma GDF15 and FGF21 levels and the resolution of T2D or obesity improvements after bariatric surgery. METHODS Plasma samples from 104 patients (52 with obesity and normoglycemia and 52 with obesity and impaired glucose tolerance or T2D) were analysed before and after Roux-en-Y-gastric bypass surgery. RESULTS Plasma GDF15 levels increased significantly after bariatric surgery in patients with obesity and normoglycemia (p < 0.01), as well as in those with obesity and impaired glucose tolerance or T2D (p < 0.05). This increase was significant in patients analysed up to 8 months after surgery in both groups (p < 0.01) but not in those analysed between 8 to 15 months after surgery, suggesting that GDF15 concentrations exhibit an early increase after surgery but may return to baseline levels over time. In contrast, plasma FGF21 levels after bariatric surgery decreased significantly in patients with impaired glucose tolerance or T2D (p < 0.05). Pre-surgery FGF21 concentrations were negatively correlated with the percentage of excess weight loss and the percentage of fat loss. CONCLUSIONS GDF15 and FGF21 exhibit a different behaviour after Roux-en-Y-gastric bypass surgery, with FGF21 being more closely associated with glycemic status and weight loss. Elevated pre-surgery FGF21 concentrations could predict a higher difficulty in losing the excess weight after surgery.
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Affiliation(s)
- Laura Salmón-Gómez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Maite Aguas-Ayesa
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Víctor Valentí
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - Rafael Moncada
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain
| | - Carolina M Perdomo
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Camilo Silva
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Escalada
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
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Liu X, Essien AE, Lu W, Jin H, Pan L, Li Y, Xiao W. Growth differentiation factor 15 as a potential diagnostic biomarker for rheumatoid arthritis : a systematic review. Bone Joint Res 2025; 14:389-397. [PMID: 40324786 PMCID: PMC12052417 DOI: 10.1302/2046-3758.145.bjr-2024-0230.r2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/07/2025] Open
Abstract
Aims This systematic review aimed to investigate the association between growth differentiation factor 15 (GDF-15) and rheumatoid arthritis (RA) disease activity, explore the differences at the genetic level, and evaluate the value of GDF-15 in diagnosing RA. Methods A comprehensive literature search was conducted using PubMed, Web of Science, Cochrane Library, and Embase on 23 August 2023. Methodological quality was independently assessed by using the Agency for Healthcare Research and Quality scale. The primary parameters analyzed were the serum GDF-15 concentration, disease activity, and diagnostic sensitivity and specificity. Results A total of 469 documents were retrieved, and five clinical studies were ultimately included. In the included studies, GDF-15 serum levels were found to be notably greater in RA patients than in healthy individuals, and these levels exhibited a positive correlation with disease severity. Furthermore, increased GDF-15 serum levels were associated with specific gene variations in RA patients, but varied according to ethnicity. In two included studies, GDF-15 showed high diagnostic sensitivity and specificity for highly active RA, demonstrating its utility as a diagnostic biomarker of RA. Conclusion GDF-15 expression is increased in RA patients and is associated with disease activity; thus, GDF-15 is potentially an effective diagnostic biomarker for RA. However, additional high-quality studies, especially randomized controlled trials and cohort studies with follow-up data, are needed to assess the role of GDF-15 in RA.
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Affiliation(s)
- Xu Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Anko E. Essien
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Wenhao Lu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Hongfu Jin
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Linyuan Pan
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wenfeng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Won CW, Kim M, Shin HE. From a Solitary Blood-Derived Biomarker to Combined Biomarkers of Sarcopenia: Experiences From the Korean Frailty and Aging Cohort Study. J Gerontol A Biol Sci Med Sci 2025; 80:glae237. [PMID: 39417263 DOI: 10.1093/gerona/glae237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Indexed: 10/19/2024] Open
Abstract
Sarcopenia is recognized as a complex and multifactorial disorder that includes nutritional deficiency, inactivity, proinflammatory status, hormonal changes, neurological degeneration, and metabolic disturbances. It's pathogenesis is not fully understood. Therefore, identifying specific biomarkers of sarcopenia will help us understand its pathophysiology. The most frequently reported blood-derived biomarkers of sarcopenia are growth factors, neuromuscular junctions, endocrine systems, mitochondrial dysfunction, inflammation-mediated and redox processes, muscle protein turnover, blood metabolomics, and behavior-mediated biomarkers. Here, we address the implications of sarcopenia biomarkers based on our research experience with Korean Frailty and Aging Cohort Study cohort data. It includes free testosterone, myostatin, fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF-15), procollagen type III N-terminal peptide (P3NP), creatinine-based biomarkers, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), brain-derived neurotrophic factor (BDNF), metabolites (proline, alanine, tryptophan), and multi-biomarker risk score. We attempted to explain the paradoxical findings of myostatin and FGF-21 levels in relation to sarcopenia. GDF-15 levels were associated with sarcopenia prevalence but not its incidence. Plasma P3NP and BDNF levels may be biomarkers of muscle quality rather than quantity. Lower erythrocyte eicosapentaenoic acid (EPA) and docosahexaenoic acid levels were associated with slow gait speed, and erythrocyte EPA levels were associated with low handgrip strength. We developed a multi-biomarker risk score for sarcopenia and found that its accuracy in diagnosing sarcopenia was higher than that of any single biomarker.
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Affiliation(s)
- Chang Won Won
- Department of Family Medicine, Elderly Frailty Sarcopenia Research Center, College of Medicine, Kyung Hee University, Kyung Hee University Medical Center, Seoul, Republic of Korea
| | - Miji Kim
- Department of Health Sciences and Technology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hyung Eun Shin
- Department of Health Sciences and Technology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
- Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, Georgia, USA
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4
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Cheng LY, Desai J, Neeson PJ. Targeting GDF-15 in cancer cachexia and immunity. Nat Med 2025; 31:1069-1070. [PMID: 40155561 DOI: 10.1038/s41591-025-03557-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Affiliation(s)
- Louise Y Cheng
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
| | - Paul J Neeson
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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5
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Zhou Y, Dou L, Wang L, Chen J, Mao R, Zhu L, Liu D, Zheng K. Growth and differentiation factor 15: An emerging therapeutic target for brain diseases. Biosci Trends 2025; 19:72-86. [PMID: 39864834 DOI: 10.5582/bst.2024.01305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Growth and differentiation factor 15 (GDF15), a member of the transforming growth factor-βsuperfamily, is considered a stress response factor and has garnered increasing attention in recent years due to its roles in neurological diseases. Although many studies have suggested that GDF15 expression is elevated in patients with neurodegenerative diseases (NDDs), glioma, and ischemic stroke, the effects of increased GDF15 expression and the potential underlying mechanisms remain unclear. Notably, many experimental studies have shown the multidimensional beneficial effects of GDF15 on NDDs, and GDF15 overexpression is able to rescue NDD-associated pathological changes and phenotypes. In glioma, GDF15 exerts opposite effects, it is both protumorigenic and antitumorigenic. The causes of these conflicting findings are not comprehensively clear, but inhibiting GDF15 is helpful for suppressing tumor progression. GDF15 is also regarded as a biomarker of poor clinical outcomes in ischemic stroke patients, and targeting GDF15 may help prevent this disease. Thus, we systematically reviewed the synthesis, transcriptional regulation, and biological functions of GDF15 and its related signaling pathways within the brain. Furthermore, we explored the potential of GDF15 as a therapeutic target and assessed its clinical applicability in interventions for brain diseases. By integrating the latest research findings, this study provides new insights into the future treatment of neurological diseases.
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Affiliation(s)
- Yingying Zhou
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Dou
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Luyao Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiajie Chen
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruxue Mao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lingqiang Zhu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dan Liu
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kai Zheng
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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6
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Borner T, Pataro AM, De Jonghe BC. Central mechanisms of emesis: A role for GDF15. Neurogastroenterol Motil 2025; 37:e14886. [PMID: 39108013 PMCID: PMC11866100 DOI: 10.1111/nmo.14886] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 02/06/2025]
Abstract
BACKGROUND Nausea and emesis are ubiquitously reported medical conditions and often present as treatment side effects along with polymorbidities contributing to detrimental life-threatening outcomes, such as poor nutrition, lower quality of life, and unfavorable patient prognosis. Growth differentiation factor 15 (GDF15) is a stress response cytokine secreted by a wide variety of cell types in response to a broad range of stressors. Circulating GDF15 levels are elevated in a range of medical conditions characterized by cachexia and malaise. In recent years, GDF15 has gained scientific and translational prominence with the discovery that its receptor, GDNF family receptor α-like (GFRAL), is expressed exclusively in the hindbrain. GFRAL activation may results in profound anorexia and body weight loss, effects which have attracted interest for the pharmacological treatment of obesity. PURPOSE This review highlights compelling emerging evidence indicating that GDF15 causes anorexia through the induction of nausea, emesis, and food aversions, which encourage a perspective on GDF15 system function in physiology and behavior beyond homeostatic energy regulation contexts. This highlights the potential role of GDF15 in the central mediation of nausea and emesis following a variety of physiological, and pathophysiological conditions such as chemotherapy-induced emesis, hyperemesis gravidarum, and cyclic vomiting syndrome.
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Affiliation(s)
- Tito Borner
- Department of Biobehavioral Health Sciences, School of NursingUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PsychiatryUniversity of Pennsylvania, Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
- Department of Biological Sciences, Human and Evolutionary Biology SectionUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Allison M. Pataro
- Department of Biobehavioral Health Sciences, School of NursingUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Bart C. De Jonghe
- Department of Biobehavioral Health Sciences, School of NursingUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PsychiatryUniversity of Pennsylvania, Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
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7
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Kim HJ, Kang SU, Kim HJ, Lee YS, Kim CH. GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression. Mol Cell Endocrinol 2025; 598:112461. [PMID: 39814165 DOI: 10.1016/j.mce.2025.112461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 01/02/2025] [Accepted: 01/11/2025] [Indexed: 01/18/2025]
Abstract
Excessive adipocyte differentiation and accumulation contribute to the development of metabolic disorders. Growth differentiation factor 15 (GDF15) plays an essential role in energy homeostasis and is considered an anti-obesity factor; however, elevated serum levels of endogenous GDF15 have been reported in certain individuals with obesity. In this study, to gain a better understanding of this complex relationship between GDF15 levels and obesity, we investigated GDF15 expression and function during adipogenesis. Compared with mice fed a normal diet, those fed a short-term high-fat diet exhibited a reduction in epididymal white adipose tissue and serum GDF15 expression. These results were confirmed in human adipose-derived stem cells that showed reduced GDF15 expression during adipogenesis differentiation. During adipogenesis, GDF15 was primarily degraded via the autophagy lysosomal pathway, and GDF15 overexpression in pre-adipocytes inhibited adipogenesis by suppressing CCAAT enhancer binding protein alpha (C/EBPα). Furthermore, whereas we detected a reduction in homologous-pairing protein 2 (HOP2) expression during adipogenesis, expression increased in response to an overexpression of GDF15. Furthermore, following knockdown of HOP2 during GDF15 overexpression, there was no suppression of C/EBPα expression. These findings indicate that GDF15 undergoes lysosomal degradation via an autophagic pathway and suppresses adipocyte differentiation via the HOP2-mediated inhibition of C/EBPα expression. Collectively, our findings indicate that GDF15 could serve as a potential therapeutic target for the treatment of metabolic disorders.
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Affiliation(s)
- Haeng Jun Kim
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Sung-Un Kang
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea
| | - Hyo Jeong Kim
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea
| | - Yun Sang Lee
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea
| | - Chul-Ho Kim
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea.
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8
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Girona J, Guardiola M, Barroso E, García-Altares M, Ibarretxe D, Plana N, Ribalta J, Amigó N, Correig X, Vázquez-Carrera M, Masana L, Rodríguez-Calvo R. GDF15 Circulating Levels Are Associated with Metabolic-Associated Liver Injury and Atherosclerotic Cardiovascular Disease. Int J Mol Sci 2025; 26:2039. [PMID: 40076667 PMCID: PMC11900571 DOI: 10.3390/ijms26052039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
There is growing evidence linking growth differentiation factor 15 (GDF15) to both metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular (CV) risk. Nevertheless, the potential relationship between circulating levels of GDF15 and key features of MASLD being predisposed to atherosclerotic CV disease is not fully unveiled. The aim of this study was to deepen into the role of circulating GDF15 levels on metabolic-associated liver injury and atherosclerotic CV disease. We determined the serum GDF15 levels in 156 participants of a metabolic patient-based cohort, and cross-sectionally explored its associations with liver injury and an advanced atherosclerotic lipoprotein profile assessed by nuclear magnetic resonance (1H-NMR). Additionally, we prospectively evaluated the association between GDF15 levels at baseline and incident atherosclerotic CV disease after a 10-year follow-up. GDF15 was related to liver injury and inflammatory hallmarks, and it increased the likelihood for liver steatosis independently of confounding factors. Likewise, GDF15 was positively associated with an atherogenic profile, particularly with the number of very-low-density lipoproteins (VLDL) particles and its cholesterol and triglyceride content, and with an indicator of subclinical atherosclerosis (i.e., carotid intima-media thickness (cIMT)). The baseline serum GDF15 levels were higher in the patients with atherosclerotic CV disease (10.6%) after a 10-year follow-up than in the individuals without CV disease. Altogether, this study provides new insights into the role of GDF15 in both MASLD and CV disease.
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Affiliation(s)
- Josefa Girona
- Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain; (J.G.); (M.G.); (D.I.); (N.P.); (J.R.); (L.M.)
- Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
| | - Montse Guardiola
- Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain; (J.G.); (M.G.); (D.I.); (N.P.); (J.R.); (L.M.)
- Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
| | - Emma Barroso
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
- Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
- Institut de Biomedicina de la Universidad de Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Barcelona, Spain
| | - María García-Altares
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
- Metabolomics Platform, Department of Electronic Engineering (DEEEA), University Rovira i Virgili, 43007 Tarragona, Spain
| | - Daiana Ibarretxe
- Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain; (J.G.); (M.G.); (D.I.); (N.P.); (J.R.); (L.M.)
- Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
| | - Núria Plana
- Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain; (J.G.); (M.G.); (D.I.); (N.P.); (J.R.); (L.M.)
- Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
| | - Josep Ribalta
- Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain; (J.G.); (M.G.); (D.I.); (N.P.); (J.R.); (L.M.)
- Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
| | - Núria Amigó
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
- Metabolomics Platform, Department of Electronic Engineering (DEEEA), University Rovira i Virgili, 43007 Tarragona, Spain
- Biosfer Teslab, 43201 Reus, Spain
- Department of Basic Medical Sciences, University Rovira i Virgili, 43201 Reus, Spain
| | - Xavier Correig
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
- Metabolomics Platform, Department of Electronic Engineering (DEEEA), University Rovira i Virgili, 43007 Tarragona, Spain
| | - Manuel Vázquez-Carrera
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
- Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
- Institut de Biomedicina de la Universidad de Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Barcelona, Spain
| | - Lluís Masana
- Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain; (J.G.); (M.G.); (D.I.); (N.P.); (J.R.); (L.M.)
- Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
| | - Ricardo Rodríguez-Calvo
- Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain; (J.G.); (M.G.); (D.I.); (N.P.); (J.R.); (L.M.)
- Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain
- Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain;
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.); (M.G.-A.); (X.C.); (M.V.-C.)
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Chen L, Luo S, Liu T, Shuai Z, Song Y, Yang Q, Wang Y, Huang H, Luo Y. Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis. J Neuroinflammation 2025; 22:44. [PMID: 39985040 PMCID: PMC11846340 DOI: 10.1186/s12974-025-03369-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 02/05/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Sepsis-associated encephalopathy (SAE) is a severe neurological condition caused by sepsis, and presents with symptoms ranging from delirium and coma to long-term cognitive dysfunction. SAE is acknowledged as a widespread brain impairment characterized by the activation of microglia. However, the specific pathological mechanisms that drive this activation are still not clearly understood. Growth differentiation factor 15 (GDF15) levels have been noted to be considerably increased in patients with sepsis, where they are linked to disease severity and can independently predict short- and long-term mortality risk. Serum levels of GDF15 have also been negatively associated with gray matter volume and predict cognitive impairment in older individuals. However, the impact of GDF15 on sepsis-induced cognitive and memory impairments, as well as the mechanisms behind these effects, are poorly understood. METHODS To examine the role of GDF15 in SAE, a sepsis model was created in adult C57BL/6J mice using intraperitoneal administration of lipopolysaccharide (LPS). GDF15 levels in plasma and cerebrospinal fluid were measured by ELISA. The anti-GDF15 monoclonal antibody ponsegromab was injected intracerebroventricularly before modeling, and cognitive and memory functions of the septic mice were assessed using fear-conditioning and novel object recognition tests. Microglial activation and phagocytosis were evaluated using immunofluorescence and Golgi staining. Additionally, an in vitro investigation of LPS-stimulated microglia was conducted to evaluate the impacts of GDF15 on inflammatory cytokine productions and microglial phagocytic activity. Mechanisms were explored using RNA sequencing, qPCR, western blotting, flow cytometry, and immunofluorescence assays. RESULTS In the cerebrospinal fluid of septic mice, levels of GDF15 were notably elevated after intraperitoneal injection of LPS. Lateral ventricular injection of the anti-GDF15 antibody alleviated both cognitive and memory impairment in the septic mice, together with microglial activation and phagocytosis in the hippocampus, thereby protecting against synaptic loss. CONCLUSION The levels of GDF15 were elevated in the brains of septic mice. Targeting GDF15 with an anti-GDF15 antibody was found to improve sepsis-induced cognitive and memory impairment by reducing the microglial inflammatory response and phagocytosis. These results indicate that GDF15 could serve as an important therapeutic target for treating SAE.
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Affiliation(s)
- Lijiao Chen
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Shiyuan Luo
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ting Liu
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhewei Shuai
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yifan Song
- School of Anesthesiology, Shandong Second Medical University, Weifang, 261053, China
| | - Qianzi Yang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ying Wang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Hongjun Huang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Yan Luo
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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10
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Sheng J, Wang J, Ma T, He P. Relationship Between MIC-1, VEGF, and TGF-β1 and Clinicopathologic Stage and Lymph Node Metastasis in Gastric Cancer. Int J Gen Med 2025; 18:955-965. [PMID: 40007699 PMCID: PMC11853773 DOI: 10.2147/ijgm.s497572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
Objective This research investigated the relationship between serum macrophage inhibitory cytokine-1 (MIC-1), vascular endothelial growth factor (VEGF), and transforming growth factor-β1 (TGF-β1) levels and clinicopathologic features, lymph node metastasis (LNM), and prognosis of gastric cancer (GC) patients. Methods The GC group (GC patients, 198 cases)) and healthy group (healthy people, 100 cases) were established. The relationship between serum MIC-1, VEGF, TGF-β1, and clinical and pathological features in GC patients was analyzed. GC patients were divided into a metastasis group (77 patients) and a non-metastasis group (121 patients) based on whether they had LNM. The factors influencing LNM in GC patients were identified. The predictive value of serum MIC-1, VEGF, and TGF-β1 for LNM in GC patients and the relationship between serum MIC-1, VEGF, TGF-β1 levels and prognosis were analyzed. Results MIC-1, VEGF, and TGF-β1 were higher in GC. Serum MIC-1, VEGF, and TGF-β1 levels were higher in GC patients with tumor diameter ≥ 3 cm, T stage of T3 and T4, low/moderate differentiation, and LNM. Multivariate Logistic regression analysis showed that TNM stage, tumor differentiation, and serum MIC-1, VEGF, and TGF-β1 levels were risk factors for LNM in GC patients. The ROC results indicated that the combination of serum MIC-1, VEGF, and TGF-β1 had the highest AUC for predicting LNM in GV patients. The median survival time of patients with low serum MIC-1, VEGF, and TGF-β1 was higher than that of patients with high serum MIC-1, VEGF, and TGF-β1 (26.13 months vs 19.24 months, 27.06 months vs 20.18 months, and 24.20 months vs 20.08 months). Conclusion The changes of serum MIC-1, VEGF and TGF-β1 levels are related to the clinicopathological characteristics of GC patients, and the elevated levels of these indices are independent risk factors affecting LNM and prognosis of GC patients.
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Affiliation(s)
- Jianyun Sheng
- General Surgery Department, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan Province, 467000, People’s Republic of China
| | - Jieshi Wang
- General Surgery Department, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan Province, 467000, People’s Republic of China
| | - Tengda Ma
- General Surgery Department, The First People’s Hospital of Pingdingshan, Pingdingshan, Henan Province, 467000, People’s Republic of China
| | - Peina He
- Pingdingshan University, Pingdingshan, Henan Province, 467000, People’s Republic of China
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11
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Smith WB, Nguyen D, Clough T, Schofield J, Kagan MR, Kompa J, He Y, Maratos-Flier E, Jamontt J, Vong L, Schwartzkopf CD, Layne JD, Usera AR, O'Donnell CJ, Heldwein KA, Streeper RS, Goldfine AB. A Growth Differentiation Factor 15 Receptor Agonist in Randomized Placebo-Controlled Trials in Healthy or Obese Persons. J Clin Endocrinol Metab 2025; 110:771-786. [PMID: 39148430 DOI: 10.1210/clinem/dgae550] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/20/2024] [Accepted: 08/14/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND Growth differentiation factor 15 (GDF15), a divergent member of the TGF-β superfamily, signals via the hindbrain glial-derived neurotrophic factor receptor alpha-like and rearranged during transfection receptor co-receptor (GFRAL-RET) complex. In nonclinical species, GDF15 is a potent anorexigen leading to substantial weight loss. MBL949 is a half-life extended recombinant human GDF15 dimer. METHODS MBL949 was evaluated in multiple nonclinical species, and then in humans, in 2 randomized and placebo-controlled clinical trials. In the phase 1, first-in-human, single ascending dose trial, MBL949 or placebo was injected subcutaneously to overweight and obese healthy volunteers (n = 65) at doses ranging from 0.03 to 20 mg. In phase 2, MBL949 or placebo was administered subcutaneously every other week for a total of 8 doses to obese participants (n = 126) in 5 different dose regimens predicted to be efficacious based on data from the phase 1 trial. RESULTS In nonclinical species, MBL949 was generally safe and effective with reduced food intake and body weight in mice, rats, dogs, and monkeys. Weight loss was primarily from reduced fat, and metabolic endpoints improved. A single ascending dose study in overweight or obese healthy adults demonstrated mean terminal half-life of 18 to 22 days and evidence of weight loss at the higher doses. In the phase 2, weight loss was minimal following biweekly dosing of MBL949 for 14 weeks. MBL949 was safe and generally tolerated in humans over the dose range tested, adverse events of the gastrointestinal system were the most frequent observed. CONCLUSION The prolonged half-life of MBL949 supports biweekly dosing in patients. MBL949 had an acceptable safety profile. The robust weight loss observed in nonclinical species did not translate to weight loss efficacy in humans.
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Affiliation(s)
- William B Smith
- Alliance for Multispecialty Research, LLC, Knoxville, TN 37909, USA
| | - David Nguyen
- Altasciences Clinical Los Angeles, Inc., Cypress, CA 90630, USA
| | - Timothy Clough
- Novartis Biomedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland
| | - Jül Schofield
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | - Mark R Kagan
- Novartis Pharmaceuticals Corporation, Cardiovascular, Renal and Metabolic, East Hanover, NJ 07936, USA
| | - Jill Kompa
- Novartis Pharmaceuticals Corporation, Cardiovascular, Renal and Metabolic, East Hanover, NJ 07936, USA
| | - YanLing He
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | | | - Joanna Jamontt
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | - Linh Vong
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | - Chad D Schwartzkopf
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | - Joseph D Layne
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | - Aimee R Usera
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | | | - Kurt A Heldwein
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | - Ryan S Streeper
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
| | - Allison B Goldfine
- Novartis Biomedical Research, Cardiovascular, Renal and Metabolic, Cambridge, MA 02139, USA
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12
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Dantzer R, Chelette B, Vichaya EG, West AP, Grossberg A. The metabolic basis of cancer-related fatigue. Neurosci Biobehav Rev 2025; 169:106035. [PMID: 39892436 PMCID: PMC11866516 DOI: 10.1016/j.neubiorev.2025.106035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/03/2025]
Abstract
Although we are all familiar with the sensation of fatigue, there are still profound divergences on what it represents and its mechanisms. Fatigue can take various forms depending on the condition in which it develops. Cancer-related fatigue is considered a symptom of exhaustion that is often present at the time of diagnosis, increases in intensity during cancer therapy, and does not always recede after completion of treatment. It is usually attributed to the inflammation induced by damage-associated molecular patterns released by tumor cells during cancer progression and in response to its treatment. In this review, we argue that it is necessary to go beyond the symptoms of fatigue to understand its nature and mechanisms. We propose to consider fatigue as a psychobiological process that regulates the behavioral activities an organism engages in to satisfy its needs, according to its physical ability to do so and to the capacity of its intermediary metabolism to exploit the resources procured by these activities. This last aspect is critical as it implies that these metabolic aspects need to be considered to understand fatigue. Based on the findings we have accumulated over several years of studying fatigue in diverse murine models of cancer, we show that energy metabolism plays a key role in the development and persistence of this condition. Cancer-related fatigue is dependent on the energy requirements of the tumor and the negative impact of cancer therapy on the mitochondrial function of the host. When inflammation is present, it adds to the organism's energy expenses. The organism needs to adjust its metabolism to the different forms of cellular stress it experiences thanks to specialized communication factors known as mitokines that act locally and at a distance from the cells in which they are produced. They induce the subjective, behavioral, and metabolic components of fatigue by acting in the brain. Therefore, the targeting of mitokines and their brain receptors offers a window of opportunity to treat fatigue when it is no longer adaptive but an obstacle to the quality of life of cancer survivors.
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Affiliation(s)
- Robert Dantzer
- Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Brandon Chelette
- Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elisabeth G Vichaya
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, USA
| | | | - Aaron Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR 97239, USA
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13
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Liu WS, You J, Chen SD, Zhang Y, Feng JF, Xu YM, Yu JT, Cheng W. Plasma proteomics identify biomarkers and undulating changes of brain aging. NATURE AGING 2025; 5:99-112. [PMID: 39653801 DOI: 10.1038/s43587-024-00753-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 10/17/2024] [Indexed: 12/15/2024]
Abstract
Proteomics enables the characterization of brain aging biomarkers and discernment of changes during brain aging. We leveraged multimodal brain imaging data from 10,949 healthy adults to estimate brain age gap (BAG), an indicator of brain aging. Proteome-wide association analysis across 4,696 participants of 2,922 proteins identified 13 significantly associated with BAG, implicating stress, regeneration and inflammation. Brevican (BCAN) (β = -0.838, P = 2.63 × 10-10) and growth differentiation factor 15 (β = 0.825, P = 3.48 × 10-11) showed the most significant, and multiple, associations with dementia, stroke and movement functions. Dysregulation of BCAN affected multiple cortical and subcortical structures. Mendelian randomization supported the causal association between BCAN and BAG. We revealed undulating changes in the plasma proteome across brain aging, and profiled brain age-related change peaks at 57, 70 and 78 years, implicating distinct biological pathways during brain aging. Our findings revealed the plasma proteomic landscape of brain aging and pinpointed biomarkers for brain disorders.
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Affiliation(s)
- Wei-Shi Liu
- Department of Neurology and National Center for Neurological diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jia You
- Institute of Science and Technology for Brain-inspired Intelligence, Fudan University, Shanghai, China
| | - Shi-Dong Chen
- Department of Neurology and National Center for Neurological diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yi Zhang
- Department of Neurology and National Center for Neurological diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian-Feng Feng
- Institute of Science and Technology for Brain-inspired Intelligence, Fudan University, Shanghai, China
- Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China
| | - Yu-Ming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
- NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
| | - Jin-Tai Yu
- Department of Neurology and National Center for Neurological diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Wei Cheng
- Department of Neurology and National Center for Neurological diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
- Institute of Science and Technology for Brain-inspired Intelligence, Fudan University, Shanghai, China.
- Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China.
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14
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Høgh S, Borgsted C, Hegaard HK, Renault KM, Ekelund K, Bruzzone SE, Clemmensen C, Klein AB, Frokjaer VG. Growth Differentiation Factor 15 during pregnancy and postpartum as captured in blood, cerebrospinal fluid and placenta: A cohort study on associations with maternal mental health. Psychoneuroendocrinology 2025; 171:107212. [PMID: 39418693 DOI: 10.1016/j.psyneuen.2024.107212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/20/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024]
Abstract
INTRODUCTION Growth Differentiation Factor 15 (GDF15) increases substantially during pregnancy and is primarily produced by the placenta. Elevated levels of GDF15 have been associated with mental health problems in non-perinatal populations, higher corticosterone levels, and decreased estrogen receptor activity. However, the role of GDF15 in mental health during the perinatal transition remains unknown. This longitudinal study is the first to evaluate pregnancy levels of GDF15 in cerebrospinal fluid (cGDF15), plasma (pGDF15) and placenta GDF15 mRNA, along with mapping plasma GDF15 (pGDF15) level changes from late pregnancy to early postpartum. Moreover, we aimed to evaluate the association between pregnancy cGDF15 levels and cortisol early postpartum, evaluate the association between pregnancy cGDF15 levels and mental health in pregnancy and postpartum, and evaluate the association between pGDF15 and estrogens and high-sensitivity C-reactive protein (CRP). METHODS We included data from 95 women scheduled for a planned cesarean section and obtained cerebrospinal fluid (CSF) and plasma levels of GDF15. We quantified GDF15 mRNA levels in placenta biopsies. Estrogens, high-sensitivity CRP, and mental health measures were further collected on the day or one day before the cesarean section. At five weeks postpartum, mental health measures and saliva samples for cortisol analyses were collected. Correlation analyses for GDF15 in CSF, plasma, and placenta mRNA were performed, along with association analyses for pregnancy cGDF15, Cortisol Awakening Response, and mental health outcomes. RESULTS We demonstrated a strong correlation between cGDF15 and pGDF15 (r=0.52; p<0.001) and found that both cGDF15 and pGDF15 correlated with placenta GDF15 mRNA*placental weight (r=0.62, p<0.001 and r=0.44, p=0.008, respectively). During late pregnancy, both estradiol (E2) and estriol (E3) were significantly associated with pGDF15 levels (E2: p=0.002; E3: p(corrected)<0.001). Finally, we found that cGDF15 levels were not associated with self-reported mental well-being or the Cortisol Awakening Response or absolute cortisol at awakening postpartum. CONCLUSION This novel study points to the unique hormonal landscape during the perinatal transition and the specific role of GDF15 in pregnancy, which appears uncoupled with perinatal mental health and cortisol outcomes. Our data also strongly imply that the overall amount of circulating GDF15 in late pregnancy is closely related to placenta size.
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Affiliation(s)
- Stinne Høgh
- Neurobiology Research Unit, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Obstetrics, Copenhagen University Hospital - Rigshospitalet, Denmark
| | - Camilla Borgsted
- Neurobiology Research Unit, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Mental Health Center Copenhagen, Copenhagen University Hospital, Denmark
| | - Hanne K Hegaard
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Obstetrics, Copenhagen University Hospital - Rigshospitalet, Denmark
| | - Kristina M Renault
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Obstetrics, Copenhagen University Hospital - Rigshospitalet, Denmark
| | - Kim Ekelund
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Anaesthesiology, Copenhagen University Hospital - Rigshospitalet, Denmark
| | - Silvia Ep Bruzzone
- Neurobiology Research Unit, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Christoffer Clemmensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anders B Klein
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Vibe G Frokjaer
- Neurobiology Research Unit, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Mental Health Center Copenhagen, Copenhagen University Hospital, Denmark.
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15
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Zhang X, Zhou CG, Ma LJ. Role of GDF-15 in diabetic nephropathy: mechanisms, diagnosis, and therapeutic potential. Int Urol Nephrol 2025; 57:169-175. [PMID: 39150600 DOI: 10.1007/s11255-024-04179-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/25/2024] [Indexed: 08/17/2024]
Abstract
PURPOSE Growth differentiation factor 15 (GDF-15) is a cytokine involved in regulating homeostasis, and its expression is up-regulated in response to injury, stress, and inflammation. This study explored the role of GDF-15 in diabetic nephropathy (DN), a severe complication of diabetes mellitus, and its potential as a biomarker for disease progression. METHODS As a member of the transforming growth factor-β superfamily, GDF-15 exhibits its renal protective functions primarily through its anti-inflammatory effects and the up-regulation of other renal protective factors. This study evaluated the association between circulating GDF-15 levels and DN progression, examining the underlying mechanisms. RESULTS Circulating GDF-15 levels are closely linked to the development and progression of DN. While existing research has yielded some consistent conclusions, a comprehensive understanding of the role of GDF-15 in DN pathogenesis is needed to identify new therapeutic targets and strategies. CONCLUSION GDF-15 has the potential to be a prognostic and diagnostic biomarker for DN. It is crucial to establish appropriate reference ranges and explore their clinical utility in routine practice for validating the role of GDF-15 in DN management. Further interventional studies are required to confirm its clinical value in diagnosing and predicting the progression of DN.
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Affiliation(s)
- Xin Zhang
- Clinical Laboratory, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201100, China
| | - Chen-Gang Zhou
- Clinical Laboratory, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201100, China
| | - Li-Jia Ma
- Clinical Laboratory, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201100, China.
- Pathology Department, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201100, China.
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16
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Takaoka M, Tadross JA, Al-Hadithi ABAK, Zhao X, Villena-Gutiérrez R, Tromp J, Absar S, Au M, Harrison J, Coll AP, Marciniak SJ, Rimmington D, Oliver E, Ibáñez B, Voors AA, O’Rahilly S, Mallat Z, Goodall JC. GDF15 antagonism limits severe heart failure and prevents cardiac cachexia. Cardiovasc Res 2024; 120:2249-2260. [PMID: 39312445 PMCID: PMC11687397 DOI: 10.1093/cvr/cvae214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 07/19/2024] [Accepted: 07/30/2024] [Indexed: 09/25/2024] Open
Abstract
AIMS Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. METHODS AND RESULTS Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. CONCLUSION Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
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Affiliation(s)
- Minoru Takaoka
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
| | - John A Tadross
- Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and Medical Research Council, University of Cambridge, Cambridge, UK
- Department of Histopathology, East Midlands & East of England Genomic Laboratory, Cambridge, UK
| | - Ali B A K Al-Hadithi
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Xiaohui Zhao
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
| | | | - Jasper Tromp
- University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
- Saw Swee Hock School of Public Health, National University of Singapore & the National University Health System, Singapore
| | - Shazia Absar
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Marcus Au
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
| | - James Harrison
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Anthony P Coll
- Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and Medical Research Council, University of Cambridge, Cambridge, UK
| | - Stefan J Marciniak
- Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Debra Rimmington
- Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and Medical Research Council, University of Cambridge, Cambridge, UK
| | - Eduardo Oliver
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Centro de Investigaciones Biologicas Margarita Salas (CIB-CSIC), Madrid, Spain
| | - Borja Ibáñez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- IIS-Hospital Fundacion Jimenez Diaz, Madrid, Spain
| | - Adriaan A Voors
- University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Stephen O’Rahilly
- Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and Medical Research Council, University of Cambridge, Cambridge, UK
| | - Ziad Mallat
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
- Paris Cardiovascular Research Center, Université Paris Cité, INSERM UMRS 970, Paris, France
| | - Jane C Goodall
- Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK
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17
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Isik FI, Thomson S, Cueto JF, Spathos J, Breit SN, Tsai VWW, Brown DA, Finney CA. A systematic review of the neuroprotective role and biomarker potential of GDF15 in neurodegeneration. Front Immunol 2024; 15:1514518. [PMID: 39737171 PMCID: PMC11682991 DOI: 10.3389/fimmu.2024.1514518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/25/2024] [Indexed: 01/01/2025] Open
Abstract
Neurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15.
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Affiliation(s)
- Finula I. Isik
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Shannon Thomson
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - John F. Cueto
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Jessica Spathos
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Samuel N. Breit
- St. Vincent’s Centre for Applied Medical Research, St. Vincent’s Hospital and Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Vicky W. W. Tsai
- St. Vincent’s Centre for Applied Medical Research, St. Vincent’s Hospital and Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - David A. Brown
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
- Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Western Sydney Local Health District, Institute for Clinical Pathology and Medical Research, NSW Health Pathology, Sydney, NSW, Australia
| | - Caitlin A. Finney
- Neuroinflammation Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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18
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Akdogan O, Turkmen S, Uyar GC, Yucel KB, Tufekci B, Gurler F, Yazici O, Ozdemir N, Ozet A, Karakaya C, Sutcuoglu O. Impact of Serum GDF-15 and IL-6 on Immunotherapy Response in Cancer: A Prospective Study. Cancers (Basel) 2024; 16:4146. [PMID: 39766045 PMCID: PMC11674841 DOI: 10.3390/cancers16244146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/07/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Immunotherapy has transformed cancer treatment; however, predicting treatment response remains challenging. Serum biomarkers can help identify patients who are most likely to benefit from immunotherapy. OBJECTIVE This study evaluates the relationship between serum growth differentiation factor 15 (GDF-15) and interleukin-6 (IL-6) levels and treatment outcomes in cancer patients undergoing second-line immunotherapy. METHODS We conducted a prospective observational study involving 85 patients with non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), or malignant melanoma treated with nivolumab. The baseline serum levels of GDF-15 and IL-6 were measured by using ELISA kits. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with cachexia as a secondary outcome. RESULTS Elevated GDF-15 levels were significantly associated with shorter PFS (HR: 0.55, 95% CI: 0.32-0.96, p = 0.032) and OS (HR: 0.47, 95% CI: 0.25-0.90, p = 0.020). Higher IL-6 levels correlated with shorter PFS, though statistical significance was not achieved. Additionally, high GDF-15 levels were linked to increased cachexia incidence (p = 0.037). CONCLUSION Our findings indicate that GDF-15 could serve as a prognostic biomarker for immunotherapy response and may also be a target for cachexia management. Further studies should explore its potential to guide clinical decision making in oncology.
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Affiliation(s)
- Orhun Akdogan
- Department of Medical Oncology, Gazi University, 06560 Ankara, Türkiye; (F.G.); (O.Y.); (N.O.); (A.O.)
| | - Sena Turkmen
- Department of Medical Biochemistry, Gazi University, 06560 Ankara, Türkiye; (S.T.); (C.K.)
| | - Galip Can Uyar
- Department of Medical Oncology, Ankara Etlik City Hospital, 06170 Ankara, Türkiye; (G.C.U.); (K.B.Y.); (O.S.)
| | - Kadriye Bir Yucel
- Department of Medical Oncology, Ankara Etlik City Hospital, 06170 Ankara, Türkiye; (G.C.U.); (K.B.Y.); (O.S.)
| | - Busra Tufekci
- Department of Internal Medicine, Gazi University, 06560 Ankara, Türkiye;
| | - Fatih Gurler
- Department of Medical Oncology, Gazi University, 06560 Ankara, Türkiye; (F.G.); (O.Y.); (N.O.); (A.O.)
| | - Ozan Yazici
- Department of Medical Oncology, Gazi University, 06560 Ankara, Türkiye; (F.G.); (O.Y.); (N.O.); (A.O.)
| | - Nuriye Ozdemir
- Department of Medical Oncology, Gazi University, 06560 Ankara, Türkiye; (F.G.); (O.Y.); (N.O.); (A.O.)
| | - Ahmet Ozet
- Department of Medical Oncology, Gazi University, 06560 Ankara, Türkiye; (F.G.); (O.Y.); (N.O.); (A.O.)
| | - Cengiz Karakaya
- Department of Medical Biochemistry, Gazi University, 06560 Ankara, Türkiye; (S.T.); (C.K.)
| | - Osman Sutcuoglu
- Department of Medical Oncology, Ankara Etlik City Hospital, 06170 Ankara, Türkiye; (G.C.U.); (K.B.Y.); (O.S.)
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19
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Şengün N, Pala R, Çınar V, Akbulut T, Larion A, Padulo J, Russo L, Migliaccio GM. Alterations in Biomarkers Associated with Cardiovascular Health and Obesity with Short-Term Lifestyle Changes in Overweight Women: The Role of Exercise and Diet. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2019. [PMID: 39768899 PMCID: PMC11727739 DOI: 10.3390/medicina60122019] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/01/2024] [Accepted: 12/04/2024] [Indexed: 01/16/2025]
Abstract
Background and Objectives: In this study, the effects of an eight-week exercise and nutrition program on blood lipids, glucose, insulin, insulin resistance (HOMA-IR), leptin, ghrelin, irisin, malondialdehyde (MDA), and Growth Differentiation Factor 15 (GDF15) in overweight women were investigated. Materials and Methods: A total of 48 women volunteers participated in this study. The participants were randomly divided into four groups: control (C), exercise (E), nutrition (N), exercise + nutrition (E + N). While no intervention was applied to group C, the other groups participated in the predetermined programs for 8 weeks. At the beginning and end of this study, body composition was measured and blood samples were taken. Results: It was determined that the body composition components, lipid profile indicators, insulin, glucose, insulin resistance, leptin, ghrelin, irisin, and MDA parameters examined in this study showed positive changes in the intervention groups. Group E had a greater effect on body muscle percentage, MDA, and irisin levels, while group N had a greater effect on blood lipids and ghrelin levels. Conclusions: As a result, it is thought that lifestyle changes are important to improve cardiovascular health and combat obesity, and that maintaining a healthy diet together with exercise may be more effective.
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Affiliation(s)
- Nezihe Şengün
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Istanbul Kültür University, Istanbul 34158, Turkey;
| | - Ragıp Pala
- Department of Coaching Education, Faculty of Sports Science, Fırat University, Elazig 23119, Turkey; (R.P.)
| | - Vedat Çınar
- Department of Physical Education and Sport, Faculty of Sports Science, Fırat University, Elazig 23119, Turkey;
| | - Taner Akbulut
- Department of Coaching Education, Faculty of Sports Science, Fırat University, Elazig 23119, Turkey; (R.P.)
| | - Alin Larion
- Faculty of Physical Education, Ovidius University of Constanta, 900029 Constanta, Romania;
| | - Johnny Padulo
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Luca Russo
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy
| | - Gian Mario Migliaccio
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Rome Open University, 00166 Rome, Italy
- Athlete Physiology, Psychology and Nutrition Unit, Maxima Performa, 20126 Milan, Italy
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20
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Salminen A. GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process. Biogerontology 2024; 26:19. [PMID: 39643709 PMCID: PMC11624233 DOI: 10.1007/s10522-024-10164-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 11/28/2024] [Indexed: 12/09/2024]
Abstract
The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging. In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process. GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of MDSCs, Tregs, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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21
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Zhang J, Sun J, Li J, Xia H. Targeting the GDF15 Signalling for Obesity Treatment: Recent Advances and Emerging Challenges. J Cell Mol Med 2024; 28:e70251. [PMID: 39700016 DOI: 10.1111/jcmm.70251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 11/06/2024] [Accepted: 11/15/2024] [Indexed: 12/21/2024] Open
Abstract
The growth differentiation factor 15 (GDF15)-glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) pathway plays a crucial role in the regulation of metabolism, appetite and body weight control. Obesity is an increasingly prevalent chronic disease worldwide, necessitating effective treatment strategies. Recent preclinical and clinical studies have highlighted that targeting the GDF15-GFRAL signalling pathway is a promising approach for treating obesity, particularly because it has minimal impact on skeletal muscle mass, which is essential to preserve during weight loss. Given its distinctive mechanisms, the GDF15-GFRAL axis represents an attractive target for addressing various metabolic disorders, especially obesity. In this review, we will explore how the GDF15-GFRAL axis is regulated, its distribution in the body and its role in the regulation of metabolism, appetite and obesity. Additionally, we will discuss recent advances and potential challenges in targeting the GDF15-GFRAL axis for obesity treatment.
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Affiliation(s)
- Jincheng Zhang
- Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center and National Clinical Research Center for Geriatrics and Laboratory of Molecular Targeted Therapy in Oncology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- School of Physical Education and Sports, Sichuan University, Chengdu, China
- Research Institute of Molecular Exercise Science, Hungarian University of Sports Science, Budapest, Hungary
| | - Jingquan Sun
- School of Physical Education and Sports, Sichuan University, Chengdu, China
| | - Jielang Li
- Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center and National Clinical Research Center for Geriatrics and Laboratory of Molecular Targeted Therapy in Oncology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hongwei Xia
- Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center and National Clinical Research Center for Geriatrics and Laboratory of Molecular Targeted Therapy in Oncology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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22
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Zhu X, Olson B, Keith D, Norgard MA, Levasseur PR, Diba P, Protzek S, Li J, Li X, Korzun T, Sattler AL, Buenafe AC, Grossberg AJ, Marks DL. GDF15 and LCN2 for early detection and prognosis of pancreatic cancer. Transl Oncol 2024; 50:102129. [PMID: 39353236 PMCID: PMC11474189 DOI: 10.1016/j.tranon.2024.102129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 08/20/2024] [Accepted: 09/13/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND The prognosis of pancreatic ductal adenocarcinomas (PDAC) remains very poor, emphasizing the critical importance of early detection, where biomarkers offer unique potential. Although growth differentiation factor 15 (GDF15) and Lipocalin 2 (LCN2) have been linked to PDAC, their precise roles as biomarkers are uncertain. METHODS Circulating levels of GDF15 and LCN2 were examined in human PDAC patients, heathy controls, and individuals with benign pancreatic diseases. Circulating levels of IL-6, CA19-9, and neutrophil-to-lymphocyte ratio (NLR) were measured for comparisons. Correlations between PDAC progression and overall survival were assessed. A mouse PDAC model was employed for comprehensive analyses, complementing the human studies by exploring associations with various metabolic and inflammatory parameters. Sensitivity and specificity of the biomarkers were evaluated. FINDINGS Our results demonstrated elevated levels of circulating GDF15 and LCN2 in PDAC patients compared to both healthy controls and individuals with benign pancreatic diseases, with higher GDF15 levels associated with disease progression and increased mortality. In PDAC mice, circulating GDF15 and LCN2 progressively increased, correlating with tumor growth, behavioral manifestations, tissue and molecular pathology, and cachexia development. GDF15 exhibited highly sensitive and specific for PDAC patients compared to CA19-9, IL-6, or NLR, while LCN2 showed even greater sensitivity and specificity in PDAC mice. Combining GDF15 and LCN2, or GDF15 and CA19-9, enhanced sensitivity and specificity. INTERPRETATION Our findings indicate that GDF15 holds promise as a biomarker for early detection and prognosis of PDAC, while LCN2 could strengthen diagnostic panels.
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Affiliation(s)
- Xinxia Zhu
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA
| | - Brennan Olson
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Medical Scientist Training program, Oregon Health & Science University, Portland, Oregon, USA; Department of Otolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Dove Keith
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA
| | - Mason A Norgard
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Peter R Levasseur
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA
| | - Parham Diba
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA; Medical Scientist Training program, Oregon Health & Science University, Portland, Oregon, USA
| | - Sara Protzek
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA
| | - Ju Li
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Xiaolin Li
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Nutritional Biology, Division of Human Nutrition, Wageningen University, Wageningen, Netherlands
| | - Tetiana Korzun
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Medical Scientist Training program, Oregon Health & Science University, Portland, Oregon, USA
| | - Ariana L Sattler
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Abigail C Buenafe
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Aaron J Grossberg
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA; Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA; Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, Oregon, USA
| | - Daniel L Marks
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
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23
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Berriel Diaz M, Rohm M, Herzig S. Cancer cachexia: multilevel metabolic dysfunction. Nat Metab 2024; 6:2222-2245. [PMID: 39578650 DOI: 10.1038/s42255-024-01167-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 10/16/2024] [Indexed: 11/24/2024]
Abstract
Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or 'wasting' of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer. Here, we describe the metabolic changes contributing to body wasting in cachexia and explain how the entangled action of both tumour-derived and host-amplified processes induces these metabolic changes. We discuss energy homeostasis and possible ways that the presence of a tumour interferes with or hijacks physiological energy conservation pathways. In that context, we highlight the role played by metabolic cross-talk mechanisms in cachexia pathogenesis. Lastly, we elaborate on the challenges and opportunities in the treatment of this devastating paraneoplastic phenomenon that arise from the complex and multifaceted metabolic cross-talk mechanisms and provide a status on current and emerging therapeutic approaches.
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Affiliation(s)
- Mauricio Berriel Diaz
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany.
- Joint Heidelberg-IDC Translational Diabetes Program, Department of Inner Medicine, Heidelberg University Hospital, Heidelberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Maria Rohm
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany.
- Joint Heidelberg-IDC Translational Diabetes Program, Department of Inner Medicine, Heidelberg University Hospital, Heidelberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Stephan Herzig
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany.
- Joint Heidelberg-IDC Translational Diabetes Program, Department of Inner Medicine, Heidelberg University Hospital, Heidelberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Chair Molecular Metabolic Control, Technical University of Munich, Munich, Germany.
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24
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Lorenz EC, Smith BH, Liang Y, Park WD, Bentall AJ, Dhala AF, Waterman AD, Kennedy CC, Hickson LJ, Rule AD, Cheville AL, LeBrasseur NK, Stegall MD. Increased Pretransplant Inflammatory Biomarkers Predict Death With Function After Kidney Transplantation. Transplantation 2024; 108:2434-2445. [PMID: 38913783 PMCID: PMC11666810 DOI: 10.1097/tp.0000000000005103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
BACKGROUND Chronic systemic inflammation is associated with mortality in patients with chronic kidney disease, cardiovascular disease, and diabetes. The goal of this study was to examine the relationship between pretransplant inflammatory biomarkers (growth differentiation factor-15 [GDF-15], interleukin-6 [IL-6], soluble tumor necrosis factor receptor-1, monokine induced by gamma interferon/chemokine [C-X-C motif] ligand 9 [MIG/CXCL9], monocyte chemoattractant protein-1, soluble FAS, tumor necrosis factor-α, interleukin-15, and interleukin-1β) and death with function (DWF) after kidney transplantation (KT). METHODS We retrospectively measured inflammatory biomarker levels in serum collected up to 1 y before KT (time from blood draw to KT was 130 ± 110 d) in recipients transplanted between January 2006 and December 2018. Kaplan-Meier estimation, Cox regression, and Gradient Boosting Machine modeling were used to examine the relationship between inflammatory biomarkers and DWF. RESULTS Our cohort consisted of 1595 KT recipients, of whom 62.9% were male and 83.2% were non-Hispanic White. Over a mean follow-up of 7.4 ± 3.9 y, 21.2% of patients (n = 338) experienced DWF. Patients with the highest quartile levels of GDF-15 (>4766 pg/mL), IL-6 (>6.11 pg/mL), and MIG/CXCL9 (> 5835 pg/mL) had increased rates of DWF, and each predicted mortality independently of the others. When adjusted for clinical factors (age, diabetes, etc), the highest quartile levels of GDF-15 and IL-6 remained independently associated with DWF. Adding inflammatory markers to a clinical Cox model improved the C-statistic for DWF from 0.727 to 0.762 using a Gradient Boosting Machine modeling approach. CONCLUSIONS These findings suggest that pre-KT serum concentrations of GDF-15, IL-6, and MIG/CXCL9 may help to risk stratify and manage patients undergoing KT and suggests that chronic inflammation may play a role in mortality in KT recipients.
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Affiliation(s)
| | - Byron H Smith
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
| | - Yun Liang
- Department of Surgery, Mayo Clinic, Rochester, MN
| | | | - Andrew J Bentall
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Atiya F Dhala
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Amy D Waterman
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Cassie C Kennedy
- Division of Pulmonary, Critical Care, and Sleep Medicine, Mayo Clinic, Rochester, MN
| | - LaTonya J Hickson
- Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL
| | - Andrew D Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Andrea L Cheville
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN
| | - Nathan K LeBrasseur
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN
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25
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Zhan C, Zhu Y, Fok MR, Jin L, Han B, Lin Y. Proteome-Wide Mendelian Randomisation Identifies Causal Links of Plasma Proteins With Periodontitis. Int Dent J 2024; 74:1258-1265. [PMID: 38729796 PMCID: PMC11551566 DOI: 10.1016/j.identj.2024.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/09/2024] [Accepted: 04/12/2024] [Indexed: 05/12/2024] Open
Abstract
OBJECTIVE Periodontitis is a complex and multifactorial disease and it is challenging to decipher its underlying causes and mechanisms. This study attempted to explore potential circulating proteins in connection to periodontitis through proteome-wide Mendelian randomisation (MR). METHODS We analysed 1722 circulating proteins to identify prospective drug targets for tackling periodontitis, using the genomic dataset from the FinnGen study. Two-sample MR was conducted to evaluate the bidirectional relationship between circulating proteins and periodontitis risk. A dataset from the UK Biobank was used to validate the findings. Single-cell analysis was performed to assess the cellular expression of the identified proteins within gingival tissues. RESULTS MR analyses found that genetically predicted circulating levels of von Willebrand factor A domain-containing 1 (von Willebrand factor A domain containing 1 [VWA1], odds ratios: 0.94, 95% CI 0.92-0.97, P = 1.28 × 10-5) were inversely associated with periodontitis. In contrast, the level of growth differentiation factor 15 (growth differentiation factor 15 [GDF15], odds ratios: 1.05, 95% CI 1.02-1.07, P = 2.12 × 10-5) might be associated with an increased risk of periodontitis. Single-cell analysis indicated that VWA1 was primarily expressed in endothelial cells of healthy gingival tissues, while the main source of GDF15 was not derived from periodontal cells. CONCLUSIONS The present study suggests that certain plasma proteins like VWA1 and GDF15 may be potentially indicative of the risk and susceptibility to periodontitis. These proteins could possibly be the potential therapeutic targets for treating periodontitis, and further investigation is highly warranted.
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Affiliation(s)
- Chaoning Zhan
- Division of Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Yuexin Zhu
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Melissa Rachel Fok
- Division of Periodontology & Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Lijian Jin
- Division of Periodontology & Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Bing Han
- Department of Orthodontics, Cranial-Facial Growth and Development Center, Peking University School and Hospital of Stomatology, Beijing, China.
| | - Yifan Lin
- Division of Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
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López-Gálvez R, Rivera-Caravaca JM, Mandaglio-Collados D, Ruiz-Alcaraz AJ, Lahoz-Tornos Á, Hernández-Romero D, Orenes-Piñero E, Ramos-Bratos MP, Martínez CM, Carpes M, Arribas-Leal JM, Cánovas S, Lip GYH, Marín F. Endothelial activation, Cell-Cell Interactions, and Inflammatory Pathways in Postoperative Atrial Fibrillation Following Cardiac Surgery. Biomed J 2024:100821. [PMID: 39603594 DOI: 10.1016/j.bj.2024.100821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 10/21/2024] [Accepted: 11/22/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Postoperative atrial fibrillation (POAF) is common after cardiac surgery and related to endothelial activation and systemic inflammation. Herein, we investigate the pathophysiological mechanisms of AF through endothelial activation and cell-cell interactions related to the development of POAF. METHODS Patients without previous AF undergoing cardiac surgery were studied. Permanent AF patients were included as positive controls. Interleukin (IL)-6, Von Willebrand factor (vWF), N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity troponin T (hsTnT) were evaluated by electrochemiluminescence. Vascular cell adhesion molecule-1 (VCAM-1) and human Growth Differentiation Factor 15 (GDF-15) was assessed by ELISA. Connexins (Cxs) 40 and 43 were measured by tissue immunolabelling, and apoptosis by TUNEL assay. RESULTS We included 117 patients (median age 67: 27.8% female): 17 with permanent AF; 27 with POAF and 73 with non- AF. Patients with permanent AF and POAF had higher levels of NT-proBNP, hs-TnT, apoptotic nuclei and decrease Cx43 expression, compared to non-AF patients (all p-value <0.05). VCAM-1 and GDF-15 were significantly higher in permanent AF vs. non-AF (p=0.013 and p=0.035). CONCLUSIONS Greater endothelial activation and inflammation in AF patients compared to those without AF was found. The proinflammatory state in AF patients, in addition to the lower expression of Cx43, seems to be associated with atrial remodeling processes occurring in AF.
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Affiliation(s)
- Raquel López-Gálvez
- Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBERCV, Murcia, Spain.
| | - José Miguel Rivera-Caravaca
- Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBERCV, Murcia, Spain; Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John and Moores University, and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom; Faculty of Nursing, University of Murcia, Murcia, Spain
| | - Darío Mandaglio-Collados
- Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBERCV, Murcia, Spain
| | - Antonio J Ruiz-Alcaraz
- Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - Álvaro Lahoz-Tornos
- Department of Cardiovascular Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Diana Hernández-Romero
- Department of Legal and Forensic Medicine, Faculty of Medicine, Regional Campus of International Excellence "Campus Mare Nostrum", Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), University of Murcia, Murcia, Spain
| | - Esteban Orenes-Piñero
- Department of Biochemistry and Molecular Biology-A, Faculty of Biology, University of Murcia, Murcia, Spain
| | - María Pilar Ramos-Bratos
- Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBERCV, Murcia, Spain
| | - Carlos M Martínez
- Pathology Core. Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Marina Carpes
- Pathology Core. Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - José María Arribas-Leal
- Department of Cardiovascular Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Sergio Cánovas
- Department of Cardiovascular Surgery, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John and Moores University, and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom; Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg Thrombosis Research Unit, Aalborg University, Denmark
| | - Francisco Marín
- Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBERCV, Murcia, Spain
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Stacchiotti S, Martini S, Pasquali S, Frezza AM, Beretta A, Percio S, Lecchi M, Tortoreto M, Barisella M, Collini P, Dagrada GP, Merlini A, Huang PH, Jenks A, Jones RL, Tap WD, Ingrosso M, Morosi C, Brich S, Giani C, Verderio P, Casali PG, Leonard H, Gronchi A, Zuco V, Zaffaroni N. GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression. Clin Cancer Res 2024; 30:5122-5137. [PMID: 39283723 PMCID: PMC11565171 DOI: 10.1158/1078-0432.ccr-23-3991] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 05/24/2024] [Accepted: 09/12/2024] [Indexed: 11/16/2024]
Abstract
PURPOSE Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness. EXPERIMENTAL DESIGN A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness. RESULTS ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness. CONCLUSIONS This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.
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Affiliation(s)
- Silvia Stacchiotti
- Medical Oncology Unit 2, Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy
| | - Silvia Martini
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Sandro Pasquali
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Anna M. Frezza
- Medical Oncology Unit 2, Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy
| | - Alessia Beretta
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Stefano Percio
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Mara Lecchi
- Unit of Bioinformatics and Biostatistics, Department Epidemiology and Data Science, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Tortoreto
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | | - Paola Collini
- Soft Tissue Tumor Pathology Unit, Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Gian Paolo Dagrada
- Soft Tissue Tumor Pathology Unit, Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | | - Paul H. Huang
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Andrew Jenks
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Robin L. Jones
- The Institute of Cancer Research, London, United Kingdom
- The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - William D. Tap
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Matilde Ingrosso
- Medical Oncology Unit 2, Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy
| | - Carlo Morosi
- Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Silvia Brich
- Soft Tissue Tumor Pathology Unit, Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Claudia Giani
- Medical Oncology Unit 2, Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy
| | - Paolo Verderio
- Unit of Bioinformatics and Biostatistics, Department Epidemiology and Data Science, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo G. Casali
- Medical Oncology Unit 2, Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy
| | - Hugh Leonard
- Chair of Trustees of the EHE Rare Cancer Charity UK, Charity Number 1162472, Kingston-Upon-Thames, United Kingdom
| | - Alessandro Gronchi
- Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Valentina Zuco
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Nadia Zaffaroni
- Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Di Pastena F, Pond G, Tsakiridis EE, Gouveia A, Ahmadi E, Biziotis OD, Ali A, Swaminath A, Okawara G, Ellis PM, Abdulkarim B, Ahmed N, Robinson A, Roa W, Valdes M, Kavsak P, Wierzbicki M, Wright J, Steinberg G, Tsakiridis T. Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy. Radiat Oncol 2024; 19:155. [PMID: 39511611 PMCID: PMC11542377 DOI: 10.1186/s13014-024-02546-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 10/23/2024] [Indexed: 11/15/2024] Open
Abstract
INTRODUCTION Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials. METHODS Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60-66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes. RESULTS Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively). CONCLUSIONS GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets.
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Affiliation(s)
- Fiorella Di Pastena
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
| | - Gregory Pond
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Ontario Clinical Oncology Group, McMaster University, Hamilton, ON, Canada
| | - Evangelia E Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
| | - Andre Gouveia
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Radiation Oncology, Juravinski Cancer Center, Hamilton Health Science, Hamilton, ON, Canada
| | - Elham Ahmadi
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Center for Discovery and Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Olga-Demetra Biziotis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Center for Discovery and Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Amr Ali
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Center for Discovery and Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Anand Swaminath
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Radiation Oncology, Juravinski Cancer Center, Hamilton Health Science, Hamilton, ON, Canada
| | - Gordon Okawara
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Radiation Oncology, Juravinski Cancer Center, Hamilton Health Science, Hamilton, ON, Canada
| | - Peter M Ellis
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | | | | | | | - Wilson Roa
- Cross Cancer Institute, Edmonton, AB, Canada
| | - Mario Valdes
- Grand River Cancer Center, Kitchener, ON, Canada
| | - Peter Kavsak
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Marcin Wierzbicki
- Radiation Physics Program, Juravinski Cancer Centre, Hamilton, ON, Canada
| | - James Wright
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Ontario Clinical Oncology Group, McMaster University, Hamilton, ON, Canada
- Radiation Oncology, Juravinski Cancer Center, Hamilton Health Science, Hamilton, ON, Canada
| | - Gregory Steinberg
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Theodoros Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.
- Department of Oncology, McMaster University, Hamilton, ON, Canada.
- Ontario Clinical Oncology Group, McMaster University, Hamilton, ON, Canada.
- Radiation Oncology, Juravinski Cancer Center, Hamilton Health Science, Hamilton, ON, Canada.
- Center for Discovery and Cancer Research, McMaster University, Hamilton, ON, Canada.
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Li X, Sun H, Zhang L, Liang H, Zhang B, Yang J, Peng X, Sun J, Zhou Y, Zhai M, Jiang L, Zhu H, Duan W. GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway. Eur J Pharmacol 2024; 982:176894. [PMID: 39147013 DOI: 10.1016/j.ejphar.2024.176894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 08/11/2024] [Accepted: 08/12/2024] [Indexed: 08/17/2024]
Abstract
Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.
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Affiliation(s)
- Xiayun Li
- College of Life Sciences, Northwest University, Xi'an, 710069, China; Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China
| | - He Sun
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China
| | - Liyun Zhang
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China
| | - Hongliang Liang
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, 94305, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305, USA
| | - Bin Zhang
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China; Department of Surgery, The 954th Hospital of the Chinese People's Liberation Army, Shannan, 856100, China
| | - Jiachang Yang
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China
| | - Xiangyan Peng
- School of Medicine, Northwest University, Xi'an, 710069, China
| | - Jingwei Sun
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China
| | - Yang Zhou
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Mengen Zhai
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China
| | - Liqing Jiang
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China.
| | - Hanzhao Zhu
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China.
| | - Weixun Duan
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, 710032, China.
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van de Lisdonk D, Li B. The area postrema: a critical mediator of brain-body interactions. Genes Dev 2024; 38:793-797. [PMID: 39362783 PMCID: PMC11535157 DOI: 10.1101/gad.352276.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
The dorsal vagal complex contains three structures: the area postrema, the nucleus tractus solitarii, and the dorsal motor nucleus of the vagus. These structures are tightly linked, both anatomically and functionally, and have important yet distinct roles in not only conveying peripheral bodily signals to the rest of the brain but in the generation of behavioral and physiological responses. Reports on the new discoveries in these structures were highlights of the symposium. In this outlook, we focus on the roles of the area postrema in mediating brain-body interactions and its potential utility as a therapeutic target, especially in cancer cachexia.
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Affiliation(s)
- Daniëlle van de Lisdonk
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
- Center for Neuroscience, University of Amsterdam, Amsterdam 1098 XH, the Netherlands
| | - Bo Li
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China
- School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China
- Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China
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Takeuchi K, Yamaguchi K, Takahashi Y, Yano K, Okishio S, Ishiba H, Tochiki N, Kataoka S, Fujii H, Iwai N, Seko Y, Umemura A, Moriguchi M, Okanoue T, Itoh Y. Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction. Sci Rep 2024; 14:23993. [PMID: 39402176 PMCID: PMC11473698 DOI: 10.1038/s41598-024-75107-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 10/01/2024] [Indexed: 10/17/2024] Open
Abstract
GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.
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Affiliation(s)
- Kento Takeuchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan.
| | - Yusuke Takahashi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Kota Yano
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Shinya Okishio
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Hiroshi Ishiba
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Nozomi Tochiki
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Seita Kataoka
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Hideki Fujii
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Naoto Iwai
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Atsushi Umemura
- Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
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Gurtan AM, Khalid S, Koch C, Khan MZ, Lamarche LB, Splawski I, Dolan E, Carrion AM, Zessis R, Clement ME, Chen Z, Lindsley LD, Chiu YH, Streeper RS, Denning DP, Goldfine AB, Doyon B, Abbasi A, Harrow JL, Tsunoyama K, Asaumi M, Kou I, Shuldiner AR, Rodriguez-Flores JL, Rasheed A, Jahanzaib M, Mian MR, Liaqat MB, Raza SS, Sultana R, Jalal A, Saeed MH, Abbas S, Memon FR, Ishaq M, Dominy JE, Saleheen D. Identification and characterization of human GDF15 knockouts. Nat Metab 2024; 6:1913-1921. [PMID: 39327531 DOI: 10.1038/s42255-024-01135-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 08/28/2024] [Indexed: 09/28/2024]
Abstract
Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3-7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous ('knockouts') and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15.
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Affiliation(s)
| | - Shareef Khalid
- Columbia University Irving Medical Center, New York, NY, USA
- Center for Non-Communicable Diseases, Karachi, Pakistan
| | | | | | | | - Igor Splawski
- Biomedical Research at Novartis, Boston, MA, USA
- Yarrow Biotechnology, New York, NY, USA
| | | | | | | | | | - Zhiping Chen
- Biomedical Research at Novartis, Boston, MA, USA
| | | | - Yu-Hsin Chiu
- Biomedical Research at Novartis, Boston, MA, USA
| | | | | | | | - Brian Doyon
- Biomedical Research at Novartis, Boston, MA, USA
- Tango Therapeutics, Boston, MA, USA
| | - Ali Abbasi
- Centre for Genomics Research, Discovery Sciences, AstraZeneca, Cambridge, UK
| | - Jennifer L Harrow
- Centre for Genomics Research, Discovery Sciences, AstraZeneca, Cambridge, UK
| | | | | | - Ikuyo Kou
- Astellas Pharma Inc., Ibaraki, Japan
| | - Alan R Shuldiner
- Regeneron Genetics Center, LLC, Regeneron Pharmaceuticals Inc., New York, NY, USA
| | | | - Asif Rasheed
- Center for Non-Communicable Diseases, Karachi, Pakistan
| | | | | | | | | | | | - Anjum Jalal
- Punjab Institute of Cardiology, Lahore, Pakistan
| | | | - Shahid Abbas
- Faisalabad Institute of Cardiology, Faisalabad, Pakistan
| | | | | | | | - Danish Saleheen
- Columbia University Irving Medical Center, New York, NY, USA.
- Center for Non-Communicable Diseases, Karachi, Pakistan.
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Breit SN, O'Rahilly S. Humans without GDF15 reassure drug developers. Nat Metab 2024; 6:1850-1851. [PMID: 39327532 DOI: 10.1038/s42255-024-01136-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
Affiliation(s)
- Samuel N Breit
- St Vincent's Centre for Applied Medical Research, St Vincent's Hospital & University of New South Wales, Sydney, New South Wales, Australia.
| | - Stephen O'Rahilly
- MRC Metabolic Diseases Unit, Institute of Metabolic Science & University of Cambridge, Cambridge, UK.
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Ianoș RD, Cozma A, Lucaciu RL, Hangan AC, Negrean V, Mercea DC, Ciulei G, Pop C, Procopciuc LM. Role of Circulating Biomarkers in Diabetic Cardiomyopathy. Biomedicines 2024; 12:2153. [PMID: 39335666 PMCID: PMC11428922 DOI: 10.3390/biomedicines12092153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/18/2024] [Accepted: 09/21/2024] [Indexed: 09/30/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has alarmingly increased in incidence in recent decades. One of the most serious complications of T2DM is diabetic cardiomyopathy (DCM), an often underrecognized yet severe condition that is a leading cause of mortality among diabetic patients. In the early stages of DCM, patients typically show no symptoms and maintain normal systolic and diastolic left ventricle function, making early detection challenging. Currently available clinical markers are often not specific enough to detect the early stage of DCM. Conventional biomarkers of cardiac mechanical stress and injury, such as natriuretic peptides (NPs) and cardiac troponin I (cTnI), have shown limited predictive value for patients with T2DM. NPs have proven efficacy in detecting diastolic dysfunction in diabetic patients when used alongside 2D echocardiography, but their utility as biomarkers is limited to symptomatic individuals. While cTnI is a reliable indicator of general cardiac damage, it is not specific to cardiac injury caused by high glucose levels or T2DM. This underscores the need for research into biomarkers that can enable early diagnosis and management of DCM to reduce mortality rates. Promising novel biomarkers that showed good performance in detecting diastolic dysfunction or heart failure in diabetic patients include galectin-3, ST2, FGF-21, IGFBP-7, GDF-15, and TGF-β. This review summarizes the current understanding of DCM biomarkers, aiming to generate new ideas for the early recognition and treatment of DCM by exploring related pathophysiological mechanisms.
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Affiliation(s)
- Raluca Diana Ianoș
- Department of Cardiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400001 Cluj-Napoca, Romania;
| | - Angela Cozma
- 4th Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania; (V.N.); (G.C.)
| | - Roxana Liana Lucaciu
- Department of Pharmaceutical Biochemistry and Clinical Laboratory, Faculty of Pharmacy, “Iuliu-Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Adriana Corina Hangan
- Department of Inorganic Chemistry, Faculty of Pharmacy, “Iuliu-Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Vasile Negrean
- 4th Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania; (V.N.); (G.C.)
| | - Delia Corina Mercea
- Department of Cardiology, Emergency County Hospital, 430031 Baia Mare, Romania; (D.C.M.); (C.P.)
| | - George Ciulei
- 4th Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania; (V.N.); (G.C.)
| | - Călin Pop
- Department of Cardiology, Emergency County Hospital, 430031 Baia Mare, Romania; (D.C.M.); (C.P.)
- Faculty of Medicine Arad, “Vasile Goldis” Western University, 310045 Arad, Romania
| | - Lucia Maria Procopciuc
- Department of Medical Biochemistry, University of Medicine and Pharmacy “Iuliu Hațieganu”, 400349 Cluj-Napoca, Romania;
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Jiang Y, Zheng Z, Zhu J, Zhang P, Li S, Fu Y, Wang F, Zhang Z, Chang T, Zhang M, Ruan B, Wang X. The role of GDF15 in attenuating noise-induced hidden hearing loss by alleviating oxidative stress. Cell Biol Toxicol 2024; 40:79. [PMID: 39289208 PMCID: PMC11408584 DOI: 10.1007/s10565-024-09912-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 08/06/2024] [Indexed: 09/19/2024]
Abstract
Noise-induced hidden hearing loss (HHL) is a newly uncovered form of hearing impairment that causes hidden damage to the cochlea. Patients with HHL do not have significant abnormalities in their hearing thresholds, but they experience impaired speech recognition in noisy environments. However, the mechanisms underlying HHL remain unclear. In this study, we developed single-cell transcriptome profiles of the cochlea of mice with HHL, detailing changes in individual cell types. Our study revealed a transient threshold shift, reduced auditory brainstem response wave I amplitude, and decreased number of ribbon synapses in HHL mice. Our findings suggest elevated oxidative stress and GDF15 expression in cochlear hair cells of HHL mice. Notably, the upregulation of GDF15 attenuated oxidative stress and auditory impairment in the cochlea of HHL mice. This suggests that a therapeutic strategy targeting GDF15 may be efficacious against HHL.
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Affiliation(s)
- Yihong Jiang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Zeyu Zheng
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Jing Zhu
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Peng Zhang
- Department of Otolaryngology, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Shaoheng Li
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Yang Fu
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Fei Wang
- Department of Aerospace Hygiene, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Zhuoru Zhang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Tong Chang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China
| | - Min Zhang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China.
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China.
- Department of Otolaryngology, Xijing Hospital, Xi'an, 710032, Shaanxi, China.
| | - Bai Ruan
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China.
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China.
| | - Xiaocheng Wang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an, 710032, Shaanxi, China.
- Department of Aviation Medicine, Xijing Hospital, Xi'an, 710032, Shaanxi, China.
- Department of Otolaryngology, Xijing Hospital, Xi'an, 710032, Shaanxi, China.
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Deng J, Pan T, Wang D, Hong Y, Liu Z, Zhou X, An Z, Li L, Alfano G, Li G, Dolcetti L, Evans R, Vicencio JM, Vlckova P, Chen Y, Monypenny J, Gomes CADC, Weitsman G, Ng K, McCarthy C, Yang X, Hu Z, Porter JC, Tape CJ, Yin M, Wei F, Rodriguez-Justo M, Zhang J, Tejpar S, Beatson R, Ng T. The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas. EMBO Mol Med 2024; 16:2080-2108. [PMID: 39103698 PMCID: PMC11393413 DOI: 10.1038/s44321-024-00105-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 06/21/2024] [Accepted: 07/03/2024] [Indexed: 08/07/2024] Open
Abstract
Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.
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Affiliation(s)
- Jinhai Deng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
- Clinical Research Centre (CRC), Medical Pathology Centre (MPC), Cancer Early Detection and Treatment Centre (CEDTC), Translational Medicine Research Centre (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, China
| | - Teng Pan
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), 518172, Shenzhen, China
| | - Dan Wang
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Yourae Hong
- Digestive Oncology Unit and Centre for Human Genetics, Universitair Ziekenhuis (UZ) Leuven, Leuven, Belgium
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xingang Zhou
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhengwen An
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Lifeng Li
- Internet Medical and System Applications of National Engineering Laboratory, Zhengzhou, China
| | - Giovanna Alfano
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Gang Li
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Luigi Dolcetti
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Rachel Evans
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Jose M Vicencio
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Petra Vlckova
- Cell Communication Lab, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK
| | - Yue Chen
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - James Monypenny
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | | | - Gregory Weitsman
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Kenrick Ng
- Department of Medical Oncology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Caitlin McCarthy
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Xiaoping Yang
- Centre of Excellence for Mass Spectrometry, Proteomics Facility, The James Black Centre, King's College London, London, UK
| | - Zedong Hu
- Digestive Oncology Unit and Centre for Human Genetics, Universitair Ziekenhuis (UZ) Leuven, Leuven, Belgium
| | - Joanna C Porter
- Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London (UCL), Rayne Building, London, UK
| | - Christopher J Tape
- Cell Communication Lab, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK
| | - Mingzhu Yin
- Clinical Research Centre (CRC), Medical Pathology Centre (MPC), Cancer Early Detection and Treatment Centre (CEDTC), Translational Medicine Research Centre (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, China
| | - Fengxiang Wei
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), 518172, Shenzhen, China
| | | | - Jin Zhang
- 3rd Department of Breast Cancer Prevention, Treatment and Research Centre, Tianjin, PR China
- Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Tianjin, PR China
- Tianjin's Clinical Research Centre for Cancer, Tianjin, PR China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China
- National Clinical Research Centre for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Sabine Tejpar
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), 518172, Shenzhen, China
| | - Richard Beatson
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.
- Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London (UCL), Rayne Building, London, UK.
- Centre for the Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, UK.
| | - Tony Ng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.
- UCL Cancer Institute, University College London, London, UK.
- Cancer Research UK City of London Centre, London, UK.
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Magalhães FMV, Pestana RMC, Ferreira CN, Silva IFO, Candido AL, Oliveira FR, Reis FM, Gomes KB. GDF-15 levels in patients with polycystic ovary syndrome treated with metformin: a combined clinical and in silico pathway analysis. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230416. [PMID: 39420932 PMCID: PMC11460967 DOI: 10.20945/2359-4292-2023-0416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 04/01/2024] [Indexed: 10/19/2024]
Abstract
Objective Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by metabolic, reproductive, and psychological manifestations. Growth and differentiation factor 15 (GDF-15) is a cytokine associated with metabolic and inflammatory disorders. Metformin is commonly used for the treatment of PCOS. We investigated the relationship between GDF-15 levels and PCOS, the effect of metformin on GDF-15 levels, and potential biologic pathways related to GDF-15. Subjects and methods The study included 35 women with PCOS and 32 women without PCOS (controls). Both groups were compared in terms of GDF-15 levels. Additional analysis was conducted on samples from 22 women with PCOS who were treated with either metformin (n = 7) or placebo (n = 15), retrieved from a previous randomized, controlled trial. Levels of GDF-15 were measured using MILLIPLEX. The biologic pathways related to GDF-15 were evaluated using the databases STRING, SIGNOR, and Pathway Commons. The statistical analysis was conducted using the software SPSS. Results Levels of GDF-15 were higher in the PCOS group compared with the non-PCOS group (p = 0.039). Among women with PCOS, GDF-15 levels were higher in those treated with metformin compared with placebo (p = 0.007). The proteins related to GDF-15 overlapped between the databases, and a significant interaction was found between GDF-15 and proteins related to PCOS and its complications, including those related to estrogen response, oxidative stress, ovarian infertility, interleukin (IL)-18, IL-4, the ratio of advanced glycation end products to their receptor (AGE/RAGE), leptin, transforming growth factor beta (TGF-β), adipogenesis, and insulin. Conclusion The findings of the present study suggest a relationship between GDF-15 and PCOS and a potential increase in GDF-15 levels with metformin treatment. An additional finding was that GDF-15 could be involved in biologic pathways related to PCOS complications.
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Affiliation(s)
- Fernanda M V Magalhães
- Faculdade de Farmácia Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Rodrigo M C Pestana
- Faculdade de Medicina Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Cláudia N Ferreira
- Colégio Técnico Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Colégio Técnico, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Ieda F O Silva
- Faculdade de Farmácia Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Ana L Candido
- Faculdade de Medicina Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Flávia R Oliveira
- Faculdade de Medicina Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Fernando M Reis
- Faculdade de Medicina Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Karina B Gomes
- Faculdade de Farmácia Universidade Federal de Minas Gerais Belo HorizonteMG Brasil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
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38
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Chan JSF, Tabatabaei Dakhili SA, Lorenzana-Carrillo MA, Gopal K, Pulente SM, Greenwell AA, Yang K, Saed CT, Stenlund MJ, Ferrari SR, Mangra-Bala IA, Shafaati T, Bhat RK, Eaton F, Overduin M, Jørgensen SB, Steinberg GR, Mulvihill EE, Sutendra G, Ussher JR. Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy. Cell Rep 2024; 43:114573. [PMID: 39093701 DOI: 10.1016/j.celrep.2024.114573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/19/2024] [Accepted: 07/17/2024] [Indexed: 08/04/2024] Open
Abstract
Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology. We observed that GDF15 treatment alleviates diastolic dysfunction in mice with T2D independent of weight loss. This cardioprotection was associated with a reduction in cardiac inflammation, which was likely mediated via indirect actions, as direct treatment of adult mouse cardiomyocytes and differentiated THP-1 human macrophages with GDF15 failed to alleviate lipopolysaccharide-induced inflammation. Therapeutic manipulation of GDF15 action may thus have utility for both obesity and diabetic cardiomyopathy.
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Affiliation(s)
- Jordan S F Chan
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Seyed Amirhossein Tabatabaei Dakhili
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Maria Areli Lorenzana-Carrillo
- Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada; Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada
| | - Keshav Gopal
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Serena M Pulente
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada
| | - Amanda A Greenwell
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Kunyan Yang
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Christina T Saed
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Magnus J Stenlund
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Sally R Ferrari
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Indiresh A Mangra-Bala
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Tanin Shafaati
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Rakesh K Bhat
- Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Farah Eaton
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Michael Overduin
- Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | | | - Gregory R Steinberg
- Centre for Metabolism, Obesity, Diabetes Research, McMaster University, Hamilton, ON L8S 4K1, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Erin E Mulvihill
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada
| | - Gopinath Sutendra
- Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada; Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada
| | - John R Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada.
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L'homme L, Sermikli BP, Haas JT, Fleury S, Quemener S, Guinot V, Barreby E, Esser N, Caiazzo R, Verkindt H, Legendre B, Raverdy V, Cheval L, Paquot N, Piette J, Legrand-Poels S, Aouadi M, Pattou F, Staels B, Dombrowicz D. Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH. Nat Commun 2024; 15:7173. [PMID: 39169003 PMCID: PMC11339436 DOI: 10.1038/s41467-024-51078-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 07/29/2024] [Indexed: 08/23/2024] Open
Abstract
Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.
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Affiliation(s)
- Laurent L'homme
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
| | - Benan Pelin Sermikli
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Joel T Haas
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Sébastien Fleury
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Sandrine Quemener
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Valentine Guinot
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Emelie Barreby
- Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Nathalie Esser
- Laboratory of Immunometabolism and Nutrition, GIGA-I3, University of Liège, Liège, Belgium
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
| | - Robert Caiazzo
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
| | - Hélène Verkindt
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
| | - Benjamin Legendre
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
| | - Violeta Raverdy
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
| | - Lydie Cheval
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
- CNRS EMR 8228-Unité Métabolisme et Physiologie Rénale, Paris, France
| | - Nicolas Paquot
- Laboratory of Immunometabolism and Nutrition, GIGA-I3, University of Liège, Liège, Belgium
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
| | - Jacques Piette
- Laboratory of Virology and Immunology, GIGA-Signal Transduction, University of Liège, Liège, Belgium
| | - Sylvie Legrand-Poels
- Laboratory of Immunometabolism and Nutrition, GIGA-I3, University of Liège, Liège, Belgium
| | - Myriam Aouadi
- Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - François Pattou
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
| | - Bart Staels
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - David Dombrowicz
- Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
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40
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Hurtado-Carneiro V, LeBaut-Ayuso Y, Velázquez E, Flores-Lamas C, Fernández-de la Rosa R, García-García L, Gómez-Oliver F, Ruiz-Albusac JM, Pozo MÁ. Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy. Heliyon 2024; 10:e35752. [PMID: 39170185 PMCID: PMC11337050 DOI: 10.1016/j.heliyon.2024.e35752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Brain glucose hypometabolism and insulin alterations are common features of many neurological diseases. Herein we sought to corroborate the brain glucose hypometabolism that develops with ageing in 12-months old Tau-VLW transgenic mice, a model of tauopathy, as well as to determine whether this model showed signs of altered peripheral glucose metabolism. Our results demonstrated that 12-old months Tau mice exhibited brain glucose hypometabolism as well as basal hyperglycemia, impaired glucose tolerance, hyperinsulinemia, and signs of insulin resistance. Then, we further studied the effect of chronic metformin treatment (9 months) in Tau-VLW mice from 9 to 18 months of age. Longitudinal PET neuroimaging studies revealed that chronic metformin altered the temporal profile in the progression of brain glucose hypometabolism associated with ageing. Besides, metformin altered the content and/or phosphorylation of key components of the insulin signal transduction pathway in the frontal cortex leading to significant changes in the content of the active forms. Thus, metformin increased the expression of pAKT-Y474 while reducing pmTOR-S2448 and pGSK3β. These changes might be related, at least partially, to a slow progression of ageing, neurological damage, and cognitive decline. Metformin also improved the peripheral glucose tolerance and the ability of the Tau-VLW mice to maintain their body weight through ageing. Altogether our study shows that the tau-VLW mice could be a useful model to study the potential interrelationship between tauopathy and central and peripheral glucose metabolism alterations. More importantly our results suggest that chronic metformin treatment may have direct beneficial central effects by post-transcriptional modulation of key components of the insulin signal transduction pathway.
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Affiliation(s)
| | - Yannick LeBaut-Ayuso
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Esther Velázquez
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Cinthya Flores-Lamas
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain
| | | | - Luis García-García
- Pluridisciplinary Institute, Complutense University, IdISSC, Madrid, Spain
- Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University, Madrid, Spain
| | - Francisca Gómez-Oliver
- Pluridisciplinary Institute, Complutense University, IdISSC, Madrid, Spain
- Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University, Madrid, Spain
| | - Juan Miguel Ruiz-Albusac
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Miguel Ángel Pozo
- Department of Physiology, Faculty of Medicine, Complutense University, Madrid, Spain
- Pluridisciplinary Institute, Complutense University, IdISSC, Madrid, Spain
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41
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Luigetti M, Vitali F, Romano A, Sciarrone MA, Guglielmino V, Ardito M, Sabino A, Servidei S, Piro G, Carbone C, Graziani F, Lillo R, Ferraro PM, Primiano G. Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: a pilot study. Sci Rep 2024; 14:18281. [PMID: 39112608 PMCID: PMC11306773 DOI: 10.1038/s41598-024-69123-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024] Open
Abstract
Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset, progressive, multisystemic condition caused by TTR pathogenic variants. Reliable biomarkers are needed to allow early diagnosis and to monitor disease severity and progression. We measured serum concentrations of growth differentiation factor-15 (GDF-15) and uromodulin (Umod) in ATTRv patients to evaluate correlations with standard markers of disease severity (FAP stage and PND score). Blood samples were collected from 16 patients diagnosed with ATTRv amyloidosis and a verified TTR variant and from 26 healthy controls. ATTRv patients were stratified by clinical phenotype (neurologic vs. mixed), genotype (V30M vs. non-V30M), and disease severity. We found significantly higher levels of serum GDF-15 in ATTRv patients compared with controls. Mean serum Umod levels were significantly lower in patients with ATTRv than controls. A positive correlation was found between serum Umod and estimated glomerular filtration rate (eGFR), while an inverse correlation was found with cystatin C levels. Conversely, GDF-15 showed a negative correlation with eGFR, and a direct correlation with cystatin C levels. No correlation was demonstrated between GDF-15 or Umod levels and traditional cardiac biomarkers. The results identify alteration of serum levels of GDF-15 and Umod in ATTRv amyloidosis.
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Affiliation(s)
- Marco Luigetti
- Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy.
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Francesca Vitali
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Angela Romano
- Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy
| | | | - Valeria Guglielmino
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Michelangelo Ardito
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Sabino
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Serenella Servidei
- Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Geny Piro
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Carmine Carbone
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesca Graziani
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Rosa Lillo
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Pietro Manuel Ferraro
- Section of Nephrology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
| | - Guido Primiano
- Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione UILDM Lazio Onlus, Rome, Italy
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42
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Kumazaki S, Hikita H, Tahata Y, Sung JH, Fukumoto K, Myojin Y, Sakane S, Murai K, Sasaki Y, Shirai K, Saito Y, Kodama T, Kakita N, Takahashi H, Toyoda H, Suda G, Morii E, Kojima T, Ebihara T, Shimizu K, Sasaki Y, Tatsumi T, Takehara T. Serum growth differentiation factor 15 is a novel biomarker with high predictive capability for liver cancer occurrence in patients with MASLD regardless of liver fibrosis. Aliment Pharmacol Ther 2024; 60:327-339. [PMID: 38828944 DOI: 10.1111/apt.18063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/21/2024] [Accepted: 05/14/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND AND AIMS Although metabolic dysfunction-associated steatotic liver disease (MASLD) patients with a Fib-4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high-risk populations requiring follow-up is needed. We explored the utility of serum levels of growth differentiation factor-15 (GDF15), a cell stress-responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. METHODS Serum GDF15 levels were measured in 518 biopsy-performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. RESULTS In the biopsy-MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib-4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high-GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib-4 index <1.3 or low-GDF15 rarely developed liver cancer, high-GDF15 patients with a Fib-4 index >1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high-GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low-GDF15 patients, whether limited to high-Fib-4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib-4 index >1.3, 2.7% had a Fib-4 index >1.3 and >1.75 ng/mL GDF15. CONCLUSIONS Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance.
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Affiliation(s)
- Shusuke Kumazaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ji Hyun Sung
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kenji Fukumoto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuta Myojin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sadatsugu Sakane
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuhiro Murai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoichi Sasaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kumiko Shirai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshinobu Saito
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naruyasu Kakita
- Department of Gastroenterology and Hepatology, Kaizuka City Hospital, Osaka, Japan
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takashi Kojima
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takeshi Ebihara
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kentaro Shimizu
- Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yutaka Sasaki
- Department of Gastroenterology, Osaka Central Hospital, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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McCarthy SF, Tucker JAL, Hazell TJ. Exercise-induced appetite suppression: An update on potential mechanisms. Physiol Rep 2024; 12:e70022. [PMID: 39187396 PMCID: PMC11347021 DOI: 10.14814/phy2.70022] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/16/2024] [Accepted: 08/16/2024] [Indexed: 08/28/2024] Open
Abstract
The first systematic reviews of the effects of exercise on appetite-regulation and energy intake demonstrated changes in appetite-regulating hormones consistent with appetite suppression and decreases in subsequent relative energy intake over a decade ago. More recently, an intensity-dependent effect and several potential mechanisms were proposed, and this review aims to highlight advances in this field. While exercise-induced appetite suppression clearly involves acylated ghrelin, glucagon-like peptide-1 may also be involved, though recent evidence suggests peptide tyrosine tyrosine may not be relevant. Changes in subjective appetite perceptions and energy intake continue to be equivocal, though these results are likely due to small sample sizes and methodological inconsistencies. Of the proposed mechanisms responsible for exercise-induced appetite suppression, lactate has garnered the most support through in vitro and in vivo rodent studies as well as a growing amount of work in humans. Other potential modulators of exercise-induced appetite suppression may include sex hormones, growth-differentiation factor 15, Lac-Phe, brain-derived neurotrophic factor, and asprosin. Research should focus on the mechanisms responsible for the changes and consider these other modulators (i.e., myokines/exerkines) of appetite to improve our understanding of the role of exercise on appetite regulation.
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Affiliation(s)
- Seth F. McCarthy
- Department of Kinesiology and Physical EducationWilfrid Laurier UniversityWaterlooOntarioCanada
| | - Jessica A. L. Tucker
- Department of Kinesiology and Physical EducationWilfrid Laurier UniversityWaterlooOntarioCanada
| | - Tom J. Hazell
- Department of Kinesiology and Physical EducationWilfrid Laurier UniversityWaterlooOntarioCanada
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Murakawa M, Nakagawa M, Nishimura H, Kaneko S, Miyoshi M, Kawai-Kitahata F, Nitta S, Tsuchiya J, Shimizu T, Watakabe K, Mochida T, Inada K, Iizuka Y, Sakai H, Sakurai Y, Sato A, Azuma S, Kawamura T, Maeyashiki C, Kurosaki M, Kusano F, Watanabe H, Kurata H, Karakama Y, Fujiwara T, Nagata Y, Tanaka T, Kakinuma S, Okamoto R, Asahina Y. High serum gamma-glutamyltransferase level after hepatitis C virus elimination is a risk factor for the development of hepatocellular carcinoma. Hepatol Res 2024. [PMID: 39073391 DOI: 10.1111/hepr.14094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/30/2024]
Abstract
AIM Gamma-glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV-specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR. METHODS This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct-acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed. RESULTS High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10-5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87-24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single-nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels. CONCLUSIONS High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication.
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Affiliation(s)
- Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hisaaki Nishimura
- Department of Public Health, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fukiko Kawai-Kitahata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Taro Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Mochida
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Iizuka
- Department of Gastroenterology and Hepatology, Kashiwa Municipal Hospital, Chiba, Japan
| | - Hideki Sakai
- Department of Gastroenterology and Hepatology, Kashiwa Municipal Hospital, Chiba, Japan
| | - Yuki Sakurai
- Department of Gastroenterology and Hepatology, Showa General Hospital, Tokyo, Japan
| | - Ayako Sato
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Seishin Azuma
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Takahiro Kawamura
- Department of Gastroenterology and Hepatology, JA Toride Medical Center, Ibaraki, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Fumihiko Kusano
- Department of Gastroenterology and Hepatology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
| | - Hideki Watanabe
- Department of Gastroenterology and Hepatology, Yokosuka Kyosai Hospital, Kanagawa, Japan
| | - Hitoshi Kurata
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan
| | - Yuko Karakama
- Department of Gastroenterology and Hepatology, Tokyo Kyosai Hospital, Tokyo, Japan
| | - Takeo Fujiwara
- Department of Public Health, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuki Nagata
- Department of Human Genetics and Disease Diversity, Tokyo Medical Dental University, Tokyo, Japan
| | - Toshihiro Tanaka
- Department of Human Genetics and Disease Diversity, Tokyo Medical Dental University, Tokyo, Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Clinical and Diagnostic Laboratory Science, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
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45
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Silva-Bermudez LS, Klüter H, Kzhyshkowska JG. Macrophages as a Source and Target of GDF-15. Int J Mol Sci 2024; 25:7313. [PMID: 39000420 PMCID: PMC11242731 DOI: 10.3390/ijms25137313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/21/2024] [Accepted: 06/23/2024] [Indexed: 07/16/2024] Open
Abstract
Growth differentiation factor 15 (GDF-15) is a multifunctional cytokine that belongs to the transforming growth factor-beta (TGF-β) superfamily. GDF-15 is involved in immune tolerance and is elevated in several acute and chronic stress conditions, often correlating with disease severity and patient prognosis in cancer172 and metabolic and cardiovascular disorders. Despite these clinical associations, the molecular mechanisms orchestrating its effects remain to be elucidated. The effects of GDF-15 are pleiotropic but cell-specific and dependent on the microenvironment. While GDF-15 expression can be stimulated by inflammatory mediators, its predominant effects were reported as anti-inflammatory and pro-fibrotic. The role of GDF-15 in the macrophage system has been increasingly investigated in recent years. Macrophages produce high levels of GDF-15 during oxidative and lysosomal stress, which can lead to fibrogenesis and angiogenesis at the tissue level. At the same time, macrophages can respond to GDF-15 by switching their phenotype to a tolerogenic one. Several GDF-15-based therapies are under development, including GDF-15 analogs/mimetics and GDF-15-targeting monoclonal antibodies. In this review, we summarize the major physiological and pathological contexts in which GDF-15 interacts with macrophages. We also discuss the major challenges and future perspectives in the therapeutic translation of GDF-15.
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Affiliation(s)
- Lina Susana Silva-Bermudez
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (L.S.S.-B.); (H.K.)
- German Red Cross Blood Service Baden-Württemberg-Hessen, 68167 Mannheim, Germany
| | - Harald Klüter
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (L.S.S.-B.); (H.K.)
- German Red Cross Blood Service Baden-Württemberg-Hessen, 68167 Mannheim, Germany
| | - Julia G. Kzhyshkowska
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (L.S.S.-B.); (H.K.)
- German Red Cross Blood Service Baden-Württemberg-Hessen, 68167 Mannheim, Germany
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46
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Li J, Hu X, Xie Z, Li J, Huang C, Huang Y. Overview of growth differentiation factor 15 (GDF15) in metabolic diseases. Biomed Pharmacother 2024; 176:116809. [PMID: 38810400 DOI: 10.1016/j.biopha.2024.116809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/18/2024] [Accepted: 05/20/2024] [Indexed: 05/31/2024] Open
Abstract
GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFβ) superfamily, its levels increase in response to cell stress and certain diseases in the serum. To exert its effects, GDF15 binds to glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL), which was firstly identified in 2017 and highly expressed in the brain stem. Many studies have demonstrated that elevated serum GDF15 is associated with anorexia and weight loss. Herein, we focus on the biology of GDF15, specifically how this circulating protein regulates appetite and metabolism in influencing energy homeostasis through its actions on hindbrain neurons to shed light on its impact on diseases such as obesity and anorexia/cachexia syndromes. It works as an endocrine factor and transmits metabolic signals leading to weight reduction effects by directly reducing appetite and indirectly affecting food intake through complex mechanisms, which could be a promising target for the treatment of energy-intake disorders.
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Affiliation(s)
- Jian Li
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, China
| | - Xiangjun Hu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Zichuan Xie
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Jiajin Li
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Chen Huang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yan Huang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China.
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Tang Y, Yao T, Tian X, Xia X, Huang X, Qin Z, Shen Z, Zhao L, Zhao Y, Diao B, Ping Y, Zheng X, Xu Y, Chen H, Qian T, Ma T, Zhou B, Xu S, Zhou Q, Liu Y, Shao M, Chen W, Shan B, Wu Y. Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy. J Exp Med 2024; 221:e20231395. [PMID: 38695876 PMCID: PMC11070642 DOI: 10.1084/jem.20231395] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 02/26/2024] [Accepted: 04/02/2024] [Indexed: 05/08/2024] Open
Abstract
Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.
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Affiliation(s)
- Yuexiao Tang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Tao Yao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xin Tian
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xintong Xia
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xingxiao Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhewen Qin
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhong Shen
- Department of Coloproctology, Hangzhou Third People’s Hospital, Hangzhou, China
| | - Lin Zhao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Yaping Zhao
- Division of Life Sciences and Medicine, Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China
| | - Bowen Diao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Ping
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxiao Zheng
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Yonghao Xu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Hui Chen
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Tao Qian
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ben Zhou
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Suowen Xu
- Division of Life Sciences and Medicine, Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China
| | - Qimin Zhou
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, The Institute for Advanced Studies, Wuhan University, Wuhan, China
| | - Mengle Shao
- CAS Key Laboratory of Molecular Virology and Immunology, The Center for Microbes, Development, and Health, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
| | - Wei Chen
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Bo Shan
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Ying Wu
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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48
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He L, Li Z, Su D, Du H, Zhang K, Zhang W, Wang S, Xie F, Qiu Y, Ma S, Shi G, Yu D, Lei X, Li W, Li M, Wang Z, Gu J, Zhang Y. Tumor Microenvironment-Responsive Nanocapsule Delivery CRISPR/Cas9 to Reprogram the Immunosuppressive Microenvironment in Hepatoma Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403858. [PMID: 38704691 PMCID: PMC11234430 DOI: 10.1002/advs.202403858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Indexed: 05/07/2024]
Abstract
Cancer immunotherapy has demonstrated significant efficacy in various tumors, but its effectiveness in treating Hepatocellular Carcinoma (HCC) remains limited. Therefore, there is an urgent need to identify a new immunotherapy target and develop corresponding intervention strategies. Bioinformatics analysis has revealed that growth differentiation factor 15 (GDF15) is highly expressed in HCC and is closely related to poor prognosis of HCC patients. The previous study revealed that GDF15 can promote immunosuppression in the tumor microenvironment. Therefore, knocking out GDF15 through gene editing could potentially reverse the suppressive tumor immune microenvironment permanently. To deliver the CRISPR/Cas9 system specifically to HCC, nanocapsules (SNC) coated with HCC targeting peptides (SP94) on their surface is utilized. These nanocapsules incorporate disulfide bonds (SNCSS) that release their contents in the tumor microenvironment characterized by high levels of glutathione (GSH). In vivo, the SNCSS target HCC cells, exert a marked inhibitory effect on HCC progression, and promote HCC immunotherapy. Mechanistically, CyTOF analysis showed favorable changes in the immune microenvironment of HCC, immunocytes with killer function increased and immunocytes with inhibitive function decreased. These findings highlight the potential of the CRISPR-Cas9 gene editing system in modulating the immune microenvironment and improving the effectiveness of existing immunotherapy approaches for HCC.
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Affiliation(s)
- Lei He
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Zhaozhao Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Danjie Su
- Department of Obstetrics and GynecologyTangdu HospitalThe Fourth Military Medical UniversityXi'an710038China
| | - Haichen Du
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
- Department of Oncology940th HospitalJoint Logistic Support ForceLanzhou730050China
| | - Kuo Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Wangqian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Shuning Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Fei Xie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Yueyuan Qiu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Shuangxin Ma
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Gege Shi
- College of Life SciencesNorthwest UniversityXi'an710069China
| | - Duo Yu
- Department of NeurosurgeryGeneral Hospital of Central Theater CommandWuhan430012China
| | - Xiaoying Lei
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Weina Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Meng Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Zhaowei Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Jintao Gu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
| | - Yingqi Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersDepartment of BiopharmaceuticsSchool of PharmacyThe Fourth Military Medical UniversityXi'an710032China
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49
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Rose AJ, Lockie SH. Stress relief of chemo illness. J Exp Med 2024; 221:e20240545. [PMID: 38709209 PMCID: PMC11075642 DOI: 10.1084/jem.20240545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2024] Open
Abstract
New studies (Tang et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20231395) describe a liver stress pathway that is activated by certain chemotherapeutic drugs, which in turn induces a peptide hormone which partially mediates the lower food intake and body weight loss during chemotherapy treatment.
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Affiliation(s)
- Adam J. Rose
- Nutrient Metabolism and Signalling Laboratory, Department of Biochemistry and Molecular Biology, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | - Sarah H. Lockie
- Appetite and Behavioural Control Group, Department of Physiology, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
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50
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Chrysafi P, Valenzuela-Vallejo L, Stefanakis K, Kelesidis T, Connelly MA, Mantzoros CS. Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans. Nat Commun 2024; 15:5190. [PMID: 38890300 PMCID: PMC11189399 DOI: 10.1038/s41467-024-49366-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.
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Affiliation(s)
- Pavlina Chrysafi
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Laura Valenzuela-Vallejo
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Konstantinos Stefanakis
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Theodoros Kelesidis
- Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 02215, USA
| | | | - Christos S Mantzoros
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
- Department of Medicine, Boston VA Healthcare System, Boston, MA, 90095, USA.
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