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Elgazzaz M, Brawley A, Moronge D, Faulkner JL. Emerging Role of Leptin in Vascular and Placental Dysfunction in Preeclampsia. Arterioscler Thromb Vasc Biol 2025; 45:585-599. [PMID: 40177777 PMCID: PMC12036005 DOI: 10.1161/atvbaha.124.321676] [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] [Indexed: 04/05/2025]
Abstract
Leptin is a well-known metabolic hormone that plays diverse roles in various body functions, including growth, reproduction, and blood pressure regulation. In pregnancy, leptin produced from the placenta is crucial for ensuring proper fetal development and angiogenesis; however, pathological increases in leptin in maternal circulation are strongly associated with vascular endothelial dysfunction and preeclampsia. Leptin has a strong role in fertility and healthy pregnancy; however, numerous clinical reports over the last 2 decades show that leptin levels pathologically increase in patients with preeclampsia independent of metabolic status (ie, obesity). Despite this strong correlation, the role of leptin in preeclampsia is largely unexplored compared with other biomarkers likely due to differences in placental leptin production among mammals. Emerging literature has recently begun to shed light on this hormone in preeclampsia pathogenesis and uncovered some key mechanisms whereby pathologically elevated leptin production leads to cardiovascular complications for pregnant women.
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Affiliation(s)
- Mona Elgazzaz
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Amalia Brawley
- Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Desmond Moronge
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Jessica L Faulkner
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
- Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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Adeva-Andany MM, Adeva-Contreras L, Carneiro-Freire N, Ameneiros-Rodríguez E, Vila-Altesor M, Calvo-Castro I. The impact of high altitude (hypobaric hypoxia) on insulin resistance in humans. J Physiol Biochem 2025; 81:35-55. [PMID: 40019670 DOI: 10.1007/s13105-025-01069-8] [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: 06/22/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025]
Abstract
Exposure to hypobaric hypoxia (high altitude) diminishes systemic tissue oxygenation. Tissue hypoxia induces insulin resistance and a metabolic switch that reduces oxidative phosphorylation and glucose storage while enhancing glycolysis. Similarly to hypobaric hypoxia, insulin resistance develops in normal humans undergoing normobaric hypoxia and in patients with obstructive sleep apnea. Following acute exposure to high altitude, insulin resistance returns to baseline values upon returning to sea level or when compensatory mechanisms restore tissue oxygenation. However, insulin resistance persists in subjects unable to achieve sufficient oxygen delivery to tissues. Likewise, long-term residents at high altitude develop persistent insulin resistance when compensatory mechanisms do not attain adequate tissue oxygenation. Among these subjects, insulin resistance may cause clinical complications, such as hypertriglyceridemia, reduced HDL-c, visceral obesity, metabolic dysfunction-associated steatotic liver disease, essential hypertension, type 2 diabetes, subclinical vascular injury, cardiovascular disease, and kidney disease. Impaired tissue oxygenation allows the stabilization of hypoxia-inducible factor-1 (HIF-1), a transcription factor that modulates the transcriptional activity of a number of genes to coordinate the physiological responses to tissue hypoxia. Among them, HIF-1 downregulates PPARG, that codes peroxisome proliferator-activated receptor-gamma (PPAR-γ) and PPARGCA, that codes PPAR-γ coactivator-1α, in order to enable insulin resistance and the metabolic switch from oxidative phosphorylation toward glycolysis.
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Affiliation(s)
- María M Adeva-Andany
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain.
| | - Lucia Adeva-Contreras
- School of Medicine, Santiago de Compostela University, Santiago de Compostela, Galicia, Spain
| | - Natalia Carneiro-Freire
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
| | - Eva Ameneiros-Rodríguez
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
| | - Matilde Vila-Altesor
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
| | - Isabel Calvo-Castro
- Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, Ferrol, 15406, Spain
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Liu S, Liu Z, Lei H, Miao YB, Chen J. Programmable Nanomodulators for Precision Therapy, Engineering Tumor Metabolism to Enhance Therapeutic Efficacy. Adv Healthc Mater 2025; 14:e2403019. [PMID: 39529548 DOI: 10.1002/adhm.202403019] [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: 08/13/2024] [Revised: 10/22/2024] [Indexed: 11/16/2024]
Abstract
Tumor metabolism is crucial in the continuous advancement and complex growth of cancer. The emerging field of nanotechnology has made significant strides in enhancing the understanding of the complex metabolic intricacies inherent to tumors, offering potential avenues for their strategic manipulation to achieve therapeutic goals. This comprehensive review delves into the interplay between tumor metabolism and various facets of cancer, encompassing its origins, progression, and the formidable challenges posed by metastasis. Simultaneously, it underscores the classification of programmable nanomodulators and their transformative impact on enhancing cancer treatment, particularly when integrated with modalities such as chemotherapy, radiotherapy, and immunotherapy. This review also encapsulates the mechanisms by which nanomodulators modulate tumor metabolism, including the delivery of metabolic inhibitors, regulation of oxidative stress, pH value modulation, nanoenzyme catalysis, nutrient deprivation, and RNA interference technology, among others. Additionally, the review delves into the prospects and challenges of nanomodulators in clinical applications. Finally, the innovative concept of using nanomodulators to reprogram metabolic pathways is introduced, aiming to transform cancer cells back into normal cells. This review underscores the profound impact that tailored nanomodulators can have on tumor metabolic, charting a path toward pioneering precision therapies for cancer.
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Affiliation(s)
- Siwei Liu
- Women & Children's Molecular Medicine Center, Department of Gynecology, Guangyuan Central Hospital, No. 16, Jingxiangzi, Lizhou District, Guangyuan, 628000, P. R. China
| | - Zhijun Liu
- Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China
| | - Huajiang Lei
- Department of Haematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610000, China
| | - Yang-Bao Miao
- Department of Haematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610000, China
| | - Jiao Chen
- Department of Haematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu, 610000, China
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Zhang BT, Li Y, Jiang QL, Jiang R, Zeng Y, Jiang J. Human adipose-derived stem cells promote migration of papillary thyroid cancer cell via leptin pathway. Ann Med 2024; 56:2419990. [PMID: 39450935 PMCID: PMC11514398 DOI: 10.1080/07853890.2024.2419990] [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: 12/08/2023] [Revised: 09/11/2024] [Accepted: 09/19/2024] [Indexed: 10/26/2024] Open
Abstract
INTRODUCTION Obesity is associated with the incidence and poor prognosis of thyroid cancer, but the mechanism is not fully understood. The aim of this study was to investigate the effects of human adipose-derived stem cells (ADSCs) on the invasion and migration of thyroid cancer cells. METHODS ADSCs-conditioned medium (ADSC-CM) was collected to culture thyroid cancer cell lines TPC-1 cells and BCPAP cells. The effects of ADSCs on thyroid cancer cell proliferation were determined by CCK8 and EdU assays, and the effects on migration were determined by Transwell and wound closure assays. Leptin neutralizing antibodies (NAB) were added to ADSC-CM to block leptin. In animal experiments, TPC-1 cells and BCPAP cells were injected into the tail vein of nude mice, and the leptin receptor antagonist peptide allo-aca was injected subcutaneously to block the leptin pathway. The number and size of metastatic lung tumours were observed after 8 weeks. RESULTS ADSC-CM significantly promoted the invasion and migration of thyroid cancer cells and upregulated their matrix metalloproteinase 2 (MMP-2) levels, while NAB with the addition of leptin reduced the invasion and migration of thyroid cancer cells and downregulated MMP-2 levels. Allo-aca treatment reduced the number of metastatic lung nodules formed by thyroid cancer cells in nude mice and reduced the diameter of metastatic lesions. CONCLUSION ADSCs upregulate MMP-2 levels of thyroid cancer cells through exocrine leptin, thereby promoting cancer cell migration, which may be one of the key mechanisms by which obesity increases the invasiveness of thyroid cancer.
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Affiliation(s)
- Bo-Tao Zhang
- Department of General Surgery (Thyroid Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Pain Medicine, Luzhou People’s Hospital, Luzhou, China
| | - Ying Li
- Department of General Surgery (Thyroid Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qi-Lan Jiang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Rui Jiang
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yang Zeng
- Department of Orthodontics, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Mirabelli M, Misiti R, Sicilia L, Brunetti FS, Chiefari E, Brunetti A, Foti DP. Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review. Int J Mol Sci 2024; 25:9802. [PMID: 39337290 PMCID: PMC11432683 DOI: 10.3390/ijms25189802] [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: 08/02/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.
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Affiliation(s)
- Maria Mirabelli
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Roberta Misiti
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy;
- Operative Unit of Clinical Pathology, “Renato Dulbecco” Hospital, 88100 Catanzaro, Italy
| | - Luciana Sicilia
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Francesco S. Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
| | - Eusebio Chiefari
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.)
- Operative Unit of Endocrinology, “Renato Dulbecco” University Hospital, 88100 Catanzaro, Italy
| | - Daniela P. Foti
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy;
- Operative Unit of Clinical Pathology, “Renato Dulbecco” Hospital, 88100 Catanzaro, Italy
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Curtis GH, Reeve RE, Crespi EJ. Leptin signaling promotes blood vessel formation in the Xenopus tail during the embryo-larval transition. Dev Biol 2024; 512:26-34. [PMID: 38705558 DOI: 10.1016/j.ydbio.2024.05.001] [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: 02/27/2024] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
The signals that regulate peripheral blood vessel formation during development are still under investigation. The hormone leptin promotes blood vessel formation, adipose tissue establishment and expansion, tumor growth, and wound healing, but the underlying mechanisms for these actions are currently unknown. We investigated whether leptin promotes angiogenesis in the developing tail fin using embryonic transgenic xflk-1:GFP Xenopus laevis, which express a green fluorescent protein on vascular endothelial cells to mark blood vessels. We found that leptin protein is expressed in endothelial cells of developing blood vessels and that leptin treatment via injection increased phosphorylated STAT3 signaling, which is indicative of leptin activation of its receptor, in blood vessels of the larval tail fin. Leptin administration via media increased vessel length, branching, and reconnection with the cardinal vein, while decreased leptin signaling via immunoneutralization had an opposing effect on vessel development. We also observed disorganization of major vessels and microvessels of the tail fin and muscle when leptin signaling was decreased. Reduced leptin signaling lowered mRNA expression of cenpk, gpx1, and mmp9, markers for cell proliferation, antioxidation, and extracellular matrix remodeling/cell migration, respectively, in the developing tail, providing insight into three possible mechanisms underlying leptin's promotion of angiogenesis. Together these results illustrate that leptin levels are correlated with embryonic angiogenesis and that leptin coordinates multiple aspects of blood vessel growth and development, showing that leptin is an important morphogen during embryonic development.
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Affiliation(s)
- Grace H Curtis
- School of Biological Sciences, Center for Reproductive Biology, Washington State University, Pullman, WA, USA, 99164.
| | - Robyn E Reeve
- School of Biological Sciences, Center for Reproductive Biology, Washington State University, Pullman, WA, USA, 99164
| | - Erica J Crespi
- School of Biological Sciences, Center for Reproductive Biology, Washington State University, Pullman, WA, USA, 99164
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Engin A. Adipose Tissue Hypoxia in Obesity: Clinical Reappraisal of Hypoxia Hypothesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:329-356. [PMID: 39287857 DOI: 10.1007/978-3-031-63657-8_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thereby, compared to lean subjects, obese individuals have almost half lower capillary density and more than half lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 alpha (HIF-1α) activity also requires phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR)-mediated signaling. Especially HIF-1α is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia contributes to several biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation, and insulin resistance (IR). Pathogenesis of obesity-related comorbidities is attributed to intermittent hypoxia (IH), which is mostly observed in visceral obesity. Proinflammatory phenotype of the adipose tissue is a crucial link between IH and the development of IR. Inhibition of adaptive unfolded protein response (UPR) in hypoxia increases β cell death. Moreover, deletion of HIF-1α worsens β cell function. Oxidative stress, as well as the release of proinflammatory cytokines/adipokines in obesity, is proportional to the severity of IH. Reactive oxygen species (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal; however, mitochondrial ROS production is required for hypoxic HIF-1α protein stabilization. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible for the dysregulated adipocytokines production in obesity. Hypoxia both inhibits adipocyte differentiation from preadipocytes and macrophage migration from the hypoxic adipose tissue. Upon reaching a hypertrophic threshold beyond the adipocyte fat loading capacity, excess extracellular matrix (ECM) components are deposited, causing fibrosis. HIF-1α initiates the whole pathological process of fibrosis and inflammation in the obese adipose tissue. In addition to stressed adipocytes, hypoxia contributes to immune cell migration and activation which further aggravates adipose tissue fibrosis. Therefore, targeting HIF-1α might be an efficient way to suppress hypoxia-induced pathological changes in the ECM. The fibrosis score of adipose tissue correlates negatively with the body mass index and metabolic parameters. Inducers of browning/beiging adipocytes and adipokines, as well as modulations of matrix remodeling enzyme inhibitors, and associated gene regulators, are potential pharmacological targets for treating obesity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Engin AB, Engin A. Next-Cell Hypothesis: Mechanism of Obesity-Associated Carcinogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:727-766. [PMID: 39287871 DOI: 10.1007/978-3-031-63657-8_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Higher body fat content is related to a higher risk of mortality, and obesity-related cancer represents approximately 40% of all cancer patients diagnosed each year. Furthermore, epigenetic mechanisms are involved in cellular metabolic memory and can determine one's predisposition to being overweight. Low-grade chronic inflammation, a well-established characteristic of obesity, is a central component of tumor development and progression. Cancer-associated adipocytes (CAA), which enhance inflammation- and metastasis-related gene sets within the cancer microenvironment, have pro-tumoral effects. Adipose tissue is a major source of the exosomal micro ribonucleic acids (miRNAs), which modulate pathways involved in the development of obesity and obesity-related comorbidities. Owing to their composition of cargo, exosomes can activate receptors at the target cell or transfer molecules to the target cells and thereby change the phenotype of these cells. Exosomes that are released into the extracellular environment are internalized with their cargo by neighboring cells. The tumor-secreted exosomes promote organ-specific metastasis of tumor cells that normally lack the capacity to metastasize to a specific organ. Therefore, the communication between neighboring cells via exosomes is defined as the "next-cell hypothesis." The reciprocal interaction between the adipocyte and tumor cell is realized through the adipocyte-derived exosomal miRNAs and tumor cell-derived oncogenic miRNAs. The cargo molecules of adipocyte-derived exosomes are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. RNA-induced silencing regulates gene expression through various mechanisms. Destabilization of DICER enzyme, which catalyzes the conversion of primary miRNA (pri-miRNA) to precursor miRNA (pre-miRNA), is an important checkpoint in cancer development and progression. Interestingly, adipose tissue in obesity and tumors share similar pathogenic features, and the local hypoxia progress in both. While hypoxia in obesity leads to the adipocyte dysfunction and metabolic abnormalities, in obesity-related cancer cases, it is associated with worsened prognosis, increased metastatic potential, and resistance to chemotherapy. Notch-interleukin-1 (IL-1)-Leptin crosstalk outcome is referred to as "NILCO effect." In this chapter, obesity-related cancer development is discussed in the context of "next-cell hypothesis," miRNA biogenesis, and "NILCO effect."
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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Geiger K, Muendlein A, Leiherer A, Gaenger S, Brandtner EM, Wabitsch M, Fraunberger P, Drexel H, Heinzle C. Myricetin attenuates hypoxia-induced inflammation in human adipocytes. Mol Biol Rep 2023; 50:9833-9843. [PMID: 37843712 DOI: 10.1007/s11033-023-08865-9] [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: 06/15/2023] [Accepted: 09/27/2023] [Indexed: 10/17/2023]
Abstract
BACKGROUND Adipose tissue hypoxia plays a crucial role in the development of chronic low-grade systemic inflammation which has been associated with the pathogenesis of obesity-related diseases. Myricetin is a natural compound present in numerous plant-based foods with presumed anti-inflammatory and beneficial health effects. The impact of this flavonoid on hypoxia-induced expression of inflammatory adipokines and hypoxia-regulated pathways is unknown so far and has been addressed in the present study. METHODS Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured with or without myricetin under normoxic and hypoxic conditions for varying time periods. The effect of hypoxia and myricetin on the expression of the investigated adipokines was measured by real-time RT-PCR. Western blot analysis was used for the detection of transcription factors involved in hypoxia-regulated pathways. RESULTS Myricetin interfered in the hypoxia-induced regulation of adipokines and the underlying pathways, which are involved in transmitting the inflammatory response. It strongly repressed hypoxia-induced expression of apelin, leptin, chemerin, asprosin, and DPP-4 and HIF-1α accumulation in the nucleus was diminished. Furthermore, the activation of the key regulators in the inflammatory response NF-κB, Akt, and CREB was suppressed by myricetin under hypoxic conditions. Myricetin also decreased hypoxia-induced accumulation of the pro-tumorigenic transcription factors Snail and Slug in the nucleus. CONCLUSION Taken together, our results indicated that myricetin regulated hypoxia-induced expression of adipokines and hypoxia-regulated pathways in human adipocytes. Our study therefore provided evidence of the anti-inflammatory effects of myricetin in hypoxia-treated human adipocytes.
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Affiliation(s)
- Kathrin Geiger
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria.
- Medical Central Laboratories, Feldkirch, Austria.
| | - Axel Muendlein
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
| | - Andreas Leiherer
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
- Medical Central Laboratories, Feldkirch, Austria
- Private University in the Principality of Liechtenstein, Triesen, Liechtenstein
| | - Stella Gaenger
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
| | - Eva Maria Brandtner
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | | | - Heinz Drexel
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
- Private University in the Principality of Liechtenstein, Triesen, Liechtenstein
- Vorarlberger Landeskrankenhausbetriebsgesellschaft, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - Christine Heinzle
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria
- Medical Central Laboratories, Feldkirch, Austria
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El Amine Z, Mauger JF, Imbeault P. Human Preadipocytes Differentiated under Hypoxia following PCB126 Exposure during Proliferation: Effects on Differentiation, Glucose Uptake and Adipokine Profile. Cells 2023; 12:2326. [PMID: 37759548 PMCID: PMC10527447 DOI: 10.3390/cells12182326] [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: 08/09/2023] [Revised: 09/09/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Persistent organic pollutants (POPs) accumulation and hypoxia are two factors proposed to adversely alter adipose tissue (AT) functions in the context of excess adiposity. Studies have shown that preadipocytes exposure to dioxin and dioxin-like POPs have the greatest deleterious impact on rodent and immortalized human preadipocyte differentiation, but evidence on human preadipocytes is lacking. Additionally, hypoxia is known to strongly interfere with the dioxin-response pathway. Therefore, we tested the effects of pre-differentiation polychlorinated biphenyl (PCB)126 exposure at 10 µM for 3 days and subsequent differentiation under hypoxia on human subcutaneous adipocytes (hSA) differentiation, glucose uptake and expression of selected metabolism- and inflammation-related genes. Pre-differentiation PCB126 exposure lowered the adenosine triphosphate (ATP) content, glucose uptake and leptin expression of mature adipocytes but had limited effects on differentiation under normoxia (21% O2). Under hypoxia (3% O2), preadipocytes ability to differentiate was significantly reduced as reflected by significant decreased lipid accumulation and downregulation of key adipocyte genes such as peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin. Hypoxia increased glucose uptake and glucose transporter 1 (GLUT1) expression but abolished the adipocytes insulin response and GLUT4 expression. The expression of pro-inflammatory adipokine interleukin-6 (IL-6) was slightly increased by both PCB126 and hypoxia, while IL-8 expression was significantly increased only following the PCB126-hypoxia sequence. These observations suggest that PCB126 does not affect human preadipocyte differentiation, but does affect the subsequent adipocytes population, as reflected by lower ATP levels and absolute glucose uptake. On the other hand, PCB126 and hypoxia exert additive effects on AT inflammation, an important player in the development of chronic diseases such as type 2 diabetes and cardiovascular diseases.
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Affiliation(s)
- Zeinab El Amine
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada; (Z.E.A.); (J.-F.M.)
| | - Jean-François Mauger
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada; (Z.E.A.); (J.-F.M.)
| | - Pascal Imbeault
- School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada; (Z.E.A.); (J.-F.M.)
- Institut du savoir Montfort, Hôpital Montfort, Ottawa, ON K1K 0T2, Canada
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Galiniak S, Podgórski R, Rachel M, Mazur A. Serum Appetite-Regulating Hormone Levels in Cystic Fibrosis Patients: Influence of the Disease Severity and the Type of Bacterial Infection-A Pilot Study. Nutrients 2023; 15:1851. [PMID: 37111072 PMCID: PMC10140826 DOI: 10.3390/nu15081851] [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: 03/28/2023] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Cystic fibrosis (CF) belongs to the most common inherited diseases. The severity of the disease and chronic bacterial infections are associated with a lower body index, undernutrition, higher number of pulmonary exacerbations, more hospital admissions, and increased mortality. The aim of our study was to determine the impact of the severity of the disease and the type of bacterial infection in 38 CF patients on the serum level of appetite-regulating hormones including leptin, ghrelin, neuropeptide Y, agouti-signaling protein, proopiomelanocortin, kisspeptin, putative protein Y, and α-melanocyte-stimulating hormone. The patients were divided according to the severity of the disease according to spirometry and the type of chronic bacterial infection. We found that leptin level was significantly higher in patients with severe CF than in patients with mild disease (20.02 ± 8.09 vs. 12.38 ± 6.03 ng/mL, p = 0.028). Furthermore, leptin level was elevated in patients with chronic infection with Pseudomonas aeruginosa compared to uninfected participants (15.74 ± 7.02 vs. 9.28 ± 1.72 ng/mL, p = 0.043). The severity of the disease and the type of bacterial infection did not affect the levels of other appetite-regulating hormones. Moreover, we found a positive correlation between pro-inflammatory interleukin-6 and leptin level (p = 0.0426, R = 0.333). Taken together, our results indicate that both the severity of the disease and the type of bacterial infection are associated with elevated leptin levels in CF patients. Future CF treatment strategies should consider possible disturbances in the hormones that regulate appetite and the factors that influence their levels.
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Affiliation(s)
- Sabina Galiniak
- Institute of Medical Sciences, Medical College, Rzeszow University, Warzywna 1a, 35-310 Rzeszow, Poland
| | - Rafał Podgórski
- Institute of Medical Sciences, Medical College, Rzeszow University, Warzywna 1a, 35-310 Rzeszow, Poland
| | - Marta Rachel
- Institute of Medical Sciences, Medical College, Rzeszow University, Warzywna 1a, 35-310 Rzeszow, Poland
- State Hospital 2 in Rzeszów, Lwowska 60, 35-301 Rzeszów, Poland
| | - Artur Mazur
- Institute of Medical Sciences, Medical College, Rzeszow University, Warzywna 1a, 35-310 Rzeszow, Poland
- State Hospital 2 in Rzeszów, Lwowska 60, 35-301 Rzeszów, Poland
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12
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Qiao L, Gao M, Yi X, Peng H, Zhang R, Yao W, Sun G, He X. Biomimetic gene editing system for precise tumor cell reprogramming and augmented tumor therapy. J Control Release 2023; 356:663-677. [PMID: 36924897 DOI: 10.1016/j.jconrel.2023.03.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 02/22/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023]
Abstract
The abnormal level of hypoxia-inducible factor-1 alpha (HIF-1α) is closely related to cancer metastasis and treatment resistance. CRISPR-Cas9-based gene editing technology has sparked profound hope to solve this issue by precise gene disruption, although the in vivo application remains hindered by the lack of a safe and efficient delivery strategy. Herein, we developed a cell membrane biomimetic core-shell system for light-controllable, precise gene editing. The inner core of the system comprises protamine for CRISPR-Cas9/sgRNA plasmid (pCas9) loading and calcium ions for efficient pCas9 transfection. The shell of the system is camouflaged by a cell membrane and modified with AS1411 aptamers for tumor targeting and photosensitizers to induce lysosomal escape and pCas9 release through reactive oxygen species production, thereby producing light-controllable enhanced gene editing. Neoplastic H1299 cells were reprogrammed using the biomimetic gene editing system upon laser irradiation with reduced VEGF and Vimentin expression, leading to enhanced antimetastatic effects. Genetic disruption of HIF-1α augmented the in vivo chemotherapeutic efficacy of paclitaxel. Our approach of using a membrane-camouflaged system combined with light augmentation provides a potential solution for the in vivo delivery of CRISPR-Cas9 as well as a feasible strategy for cancer therapy.
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Affiliation(s)
- Lei Qiao
- Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, China
| | - Min Gao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Xiaoqing Yi
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
| | - Hui Peng
- School of Life Sciences, Anhui Medical University, Hefei 230032, China
| | - Ruijie Zhang
- School of Life Sciences, Anhui Medical University, Hefei 230032, China
| | - Wanqing Yao
- School of Life Sciences, Anhui Medical University, Hefei 230032, China
| | - Gengyun Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Xiaoyan He
- School of Life Sciences, Anhui Medical University, Hefei 230032, China.
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High oxygen-modified packaging (HiOx-MAP) mediates HIF-1α regulation of tenderness changes during postmortem aging of yak meat. Food Chem X 2023; 17:100573. [PMID: 36845525 PMCID: PMC9945635 DOI: 10.1016/j.fochx.2023.100573] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 01/10/2023] Open
Abstract
In the present study, we studied the effect of high oxygen-modified packaging (HiOx-MAP) on yak meat tenderness and the underlying mechanism. HiOx-MAP significantly increased the myofibril fragmentation index (MFI) of yak meat. In addition, western blotting showed that the expression of hypoxia-inducible factor (HIF-1α) and ryanodine receptors (RyR) in the HiOx-MAP group was reduced. HiOx-MAP increased the activity of sarcoplasmic reticulum calcium-ATPase (SERCA). The energy disperse spectroscopy (EDS) mapping showed gradually reduced calcium distribution in the treated endoplasmic reticulum. Furthermore, HiOx-MAP treatment increased the caspase-3 activity and the apoptosis rate. The activity of calmodulin protein (CaMKKβ) and AMP-activated protein kinase (AMPK) was down-regulated leading to apoptosis. These results indicated that HiOx-MAP promoted apoptosis during postmortem aging to improve the tenderization of meat.
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14
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Morais JBS, Dias TMDS, Cardoso BEP, de Paiva Sousa M, Sousa TGVD, Araújo DSCD, Marreiro DDN. Adipose Tissue Dysfunction: Impact on Metabolic Changes? Horm Metab Res 2022; 54:785-794. [PMID: 35952684 DOI: 10.1055/a-1922-7052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Adipose tissue is a metabolically dynamic organ that is the primary site of storage for excess energy, but it serves as an endocrine organ capable of synthesizing a number of biologically active compounds that regulate metabolic homeostasis. However, when the capacity of expansion of this tissue exceeds, dysfunction occurs, favoring ectopic accumulation of fat in the visceral, which has been implicated in several disease states, most notably obesity. This review highlights the mechanisms involved in the structure of adipose tissue, tissue expandability, adipocyte dysfunction, as well as the impact of these events on the manifestation of important metabolic disorders associated with adipose tissue dysfunction. A literature search using Pubmed, Web of Science, Scopus, and Cochrane databases were used to identify relevant studies, using clinical trials, experimental studies in animals and humans, case-control studies, case series, letters to the editor, and review articles published in English, without restrictions on year of publication. The excessive ectopic lipid accumulation leads to local inflammation and insulin resistance. Indeed, overnutrition triggers uncontrolled inflammatory responses white adipose tissue, leading to chronic low-grade inflammation, therefore fostering the progression of important metabolic disorders. Thus, it is essential to advance the understanding of the molecular mechanisms involved in adipose tissue dysfunction in order to mitigate the negative metabolic consequences of obesity.
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15
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Docosahexaenoic Acid Counteracts the Hypoxic-Induced Inflammatory and Metabolic Alterations in 3T3-L1 Adipocytes. Nutrients 2022; 14:nu14214600. [PMID: 36364860 PMCID: PMC9659308 DOI: 10.3390/nu14214600] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/15/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
Background: Hypoxia is caused by the excessive expansion of the white adipose tissue (AT) and is associated with obesity-related conditions such as insulin resistance, inflammation, and oxidative stress. Docosahexaenoic acid (DHA) is an omega-3 fatty acid reported to have beneficial health effects. However, the effects of DHA in AT against hypoxia-induced immune-metabolic perturbations in adipocytes exposed to low O2 tension are not well known. Consequently, this study aimed to evaluate the impact of DHA on markers of inflammation, metabolism, apoptosis, and oxidative stress in 3T3-L1 cell adipocytes exposed to low O2 tension (1% O2) induced hypoxia. Methods: The apoptosis and reactive oxygen species (ROS) rates were evaluated. Metabolic parameters such as lactate, FFA, glycerol release, glucose uptake, and ATP content were assessed by a fluorometer. The expression of HIF-1, GLUT1 and the secretion of adipocytokines such as leptin, adiponectin, and pro-inflammatory markers was evaluated. Results: DHA-treated hypoxic cells showed significantly decreased basal free fatty acid release, lactate production, and enhanced glucose consumption. In addition, DHA-treatment of hypoxic cells caused a significant reduction in the apoptosis rate and ROS production with decreased lipid peroxidation. Moreover, DHA-treatment of hypoxic cells caused a decreased secretion of pro-inflammatory markers (IL-6, MCP-1) and leptin and increased adiponectin secretion compared with hypoxic cells. Furthermore, DHA-treatment of hypoxic cells caused significant reductions in the expression of genes related to hypoxia (HIF-1, HIF-2), anaerobic metabolism (GLUT1 and Ldha), ATP production (ANT2), and fat metabolism (FASN and PPARY). Conclusion: This study suggests that DHA can exert potential anti-obesity effects by reducing the secretion of inflammatory adipokines, oxidative stress, lipolysis, and apoptosis.
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Abstract
I had been working on the endocrine and signalling role of white adipose tissue (WAT) since 1994 following the identification of the ob (Lep) gene(1), this after some 15 years investigating the physiological role of brown adipose tissue. The ob gene, a mutation in which it is responsible for the profound obesity of ob/ob (Lepob/Lepob) mice, is expressed primarily in white adipocytes and encodes the pleiotropic hormone leptin. The discovery of this adipocyte hormone had wide-ranging implications, including that white fat has multiple functions that far transcend the traditional picture of a simple lipid storage organ.
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17
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Gallo M, Adinolfi V, Barucca V, Prinzi N, Renzelli V, Barrea L, Di Giacinto P, Ruggeri RM, Sesti F, Arvat E, Baldelli R, Arvat E, Colao A, Isidori A, Lenzi A, Baldell R, Albertelli M, Attala D, Bianchi A, Di Sarno A, Feola T, Mazziotti G, Nervo A, Pozza C, Puliani G, Razzore P, Ramponi S, Ricciardi S, Rizza L, Rota F, Sbardella E, Zatelli MC. Expected and paradoxical effects of obesity on cancer treatment response. Rev Endocr Metab Disord 2021; 22:681-702. [PMID: 33025385 DOI: 10.1007/s11154-020-09597-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/25/2020] [Indexed: 12/12/2022]
Abstract
Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.
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Affiliation(s)
- Marco Gallo
- Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, AOU Città della Salute e della Scienza di Torino, Via Genova, 3, 10126, Turin, Italy.
| | - Valerio Adinolfi
- Endocrinology and Diabetology Unit, ASL Verbano Cusio Ossola, Domodossola, Italy
| | - Viola Barucca
- Oncology Unit, Department of Oncology and Medical Specialities, AO San Camillo-Forlanini, Rome, Italy
| | - Natalie Prinzi
- ENETS Center of Excellence, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori Milano, Milan, Italy
| | - Valerio Renzelli
- Department of Experimental Medicine, AO S. Andrea, Sapienza University of Rome, Rome, Italy
| | - Luigi Barrea
- Endocrinology Unit, Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy
| | - Paola Di Giacinto
- Endocrinology Unit, Department of Oncology and Medical Specialities, AO San Camillo-Forlanini, Rome, Italy
| | - Rosaria Maddalena Ruggeri
- Endocrine Unit, Department of Clinical and Experimental Medicine, University of Messina, AOU Policlinico G. Martino, Messina, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Emanuela Arvat
- Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, AOU Città della Salute e della Scienza di Torino, Via Genova, 3, 10126, Turin, Italy
| | - Roberto Baldelli
- Endocrinology Unit, Department of Oncology and Medical Specialities, AO San Camillo-Forlanini, Rome, Italy
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18
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Milan G, Conci S, Sanna M, Favaretto F, Bettini S, Vettor R. ASCs and their role in obesity and metabolic diseases. Trends Endocrinol Metab 2021; 32:994-1006. [PMID: 34625375 DOI: 10.1016/j.tem.2021.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/23/2021] [Accepted: 09/03/2021] [Indexed: 01/04/2023]
Abstract
We describe adipose stromal/stem cells (ASCs) in the structural/functional context of the adipose tissue (AT) stem niche (adiponiche), including cell-cell interactions and the microenvironment, and emphasize findings obtained in humans and in lineage-tracing models. ASCs have distinctive markers, 'colors', and anatomical 'locations' which influence their functions. Each adiponiche component can become impaired, thereby contributing to the pathological AT alterations seen in obesity and metabolic diseases. We discuss adiposopathy with a focus on adiponiche dysfunction, and underline the mechanisms that control AT expansion and energy balance. Better understanding of adiponiche regulation and ASC features could help to identify therapeutic targets that favor weight loss and counteract weight regain, and also contribute to innovative strategies for regenerative medicine.
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Affiliation(s)
- Gabriella Milan
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy.
| | - Scilla Conci
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Marta Sanna
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Francesca Favaretto
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Silvia Bettini
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
| | - Roberto Vettor
- Department of Medicine, University of Padua, Internal Medicine 3, 35128 Padua, Italy; Center for the Study and the Integrated Treatment of Obesity, Padua Hospital, 35128 Padua, Italy
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19
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Bakshi A, Singh R, Rai U. Trajectory of leptin and leptin receptor in vertebrates: Structure, function and their regulation. Comp Biochem Physiol B Biochem Mol Biol 2021; 257:110652. [PMID: 34343670 DOI: 10.1016/j.cbpb.2021.110652] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 06/23/2021] [Accepted: 07/29/2021] [Indexed: 12/11/2022]
Abstract
The present review provides a comparative insight into structure, function and control of leptin system in fishes, herptiles, birds and mammals. In general, leptin acts as an anorexigenic hormone since its administration results in decrease of food intake in vertebrates. Nonetheless, functional paradox arises in fishes from contradictory observations on level of leptin during fasting and re-feeding. In addition, leptin is shown to modulate metabolic functions in fishes, reptiles, birds and mammals. Leptin also regulates reproductive and immune functions though more studies are warranted in non-mammalian vertebrates. The expression of leptin and its receptor is influenced by numerous factors including sex steroids, stress and stress-induced catecholamines and glucocorticoids though their effect in non-mammalian vertebrates is hard to be generalized due to limited studies.
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Affiliation(s)
- Amrita Bakshi
- Department of Zoology, University of Delhi, Delhi 110007, India
| | - Rajeev Singh
- Satyawati College, University of Delhi, Delhi 110052, India
| | - Umesh Rai
- Department of Zoology, University of Delhi, Delhi 110007, India.
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20
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Gao J, Zhu J, Zhao Y, Gan X, Yu H. Leptin attenuates hypoxia-induced apoptosis in human periodontal ligament cells via the reactive oxygen species-hypoxia-inducible factor-1α pathway. Exp Physiol 2021; 106:1752-1761. [PMID: 34143536 DOI: 10.1113/ep089324] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 06/17/2021] [Indexed: 02/05/2023]
Abstract
NEW FINDINGS What is the central question of this study? Does leptin have an effect on hypoxia-induced apoptosis in human periodontal ligament cells (hPDLCs), and what is the potential underlying mechanism? What is the main finding and its importance? Hypoxia induces cell apoptosis and leptin expression in hPDLCs through the induction of hypoxia-inducible factor-1α and accumulation of reactive oxygen species (ROS). Leptin shows feedback inhibition on hypoxia-induced ROS-mediated apoptosis in hPDLCs, suggesting a new application of leptin for hypoxic damage in periodontal diseases. ABSTRACT Hypoxia-induced apoptosis of human periodontal ligament cells (hPDLCs) is an important contributor to the progression of various periodontal diseases. Although leptin has been shown to protect connective tissue cells against hypoxia-induced injury, whether it might do so by attenuating hypoxia-induced apoptosis in hPDLCs remains unclear. Here, using CoCl2 treatment, we simulated hypoxic conditions in hPDLCs and explored whether apoptosis and reactive oxygen species (ROS) levels were related to hypoxia. After small interfering RNA (siRNA) inhibition of leptin and hypoxia-inducible factor-1α (HIF-1α), the levels of apoptosis, ROS and leptin expression were measured. We showed that in CoCl2 -treated hPDLCs, significantly higher cell apoptosis rates and ROS accumulation were observed. Cobalt chloride also increased leptin and HIF-1α expression in hPDLCs. Further investigation of the pathway demonstrated that inhibition of ROS attenuated hypoxia-induced cell apoptosis and leptin expression, whereas siRNA inhibition of leptin aggravated hypoxia-induced cell apoptosis and ROS accumulation. Hypoxia induces cell apoptosis and leptin expression in hPDLCs through the induction of ROS and HIF-1α pathways, and leptin shows feedback inhibition on ROS-mediated apoptosis in hPDLCs. These findings suggest a new application of leptin for hypoxic damage in periodontal diseases.
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Affiliation(s)
- Jing Gao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Junfei Zhu
- Stomatology Center, China Japan Friendship Hospital, Beijing, 100029, China
| | - Yuwei Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xueqi Gan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Haiyang Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
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21
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Pourdashti S, Faridi N, Yaghooti H, Jalali MT, Soroush A, Bathaie SZ. Possible role of WNT10B in increased proliferation and tubule formation of human umbilical vein endothelial cell cultures treated with hypoxic conditioned medium from human adipocytes. Biotech Histochem 2021; 97:168-179. [PMID: 34044678 DOI: 10.1080/10520295.2021.1923801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Regulation of angiogenesis plays an important role in adipose tissue expansion and function. The Wnt pathway and WNT10B, the main member of Wnt family, participate in angiogenesis in cancer tumors, but there is limited evidence to support the regulatory role of WNT10B in human adipose tissue angiogenesis. Subcutaneous white adipose tissue (scWAT) of 80 participants including obese and non-obese subjects was obtained and the expression of WNT10B and VEGFA genes were evaluated using qPCR. Human adipose-derived stem cells (hADSC) were differentiated to adipocytes and incubated under either hypoxic or normoxic conditions. The conditioned media of these adipocytes were collected and used as growth media for human umbilical vein endothelial cells (HUVEC) in Matrigel. We evaluated the proliferation, cell cycle phases, tubule formation and β-catenin activation of these treated cells. We found a significant correlation between WNT10B and VEGFA expression in the scWAT of both obese and non-obese subjects. Proliferation and tubule formation of HUVEC treated with conditioned media of hypoxic adipocytes (hCM) in the S-phase were increased significantly compared to the HUVEC treated with the conditioned media of normoxic adipocytes (nCM). The expression of WNT10B and VEGFA was enhanced in hypoxic adipocytes compared to normoxic adipocytes; also, activation and nuclear translocation of β-catenin was enhanced in the HUVEC treated with hCM compared to nCM. WNT10B acts as an angiogenic protein in scWAT under hypoxic conditions. Hypoxia induced WNT10B increases VEGFA expression and causes tube formation by HUVECs and angiogenesis in adipose tissue via the canonical Wnt/β-catenin pathway.
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Affiliation(s)
- Sara Pourdashti
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran
| | - Nassim Faridi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran
| | - Hamid Yaghooti
- Cellular and Molecular Research Center and Hyperlipidemia Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad-Taha Jalali
- Hyperlipidemia Research Center and Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
| | - Ahmadreza Soroush
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - S Zahra Bathaie
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran
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22
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Blanco AM, Soengas JL. Leptin signalling in teleost fish with emphasis in food intake regulation. Mol Cell Endocrinol 2021; 526:111209. [PMID: 33588023 DOI: 10.1016/j.mce.2021.111209] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/14/2021] [Accepted: 02/05/2021] [Indexed: 12/13/2022]
Abstract
Leptin, the product of the obese (ob or Lep) gene, was first cloned in teleost fish in 2005, more than a decade after its identification in mammals. This was because bony fish and mammalian leptins share a very low amino acid sequence identity, which suggests different functionality of the leptin system in fish compared to that of mammals. Indeed, major differences are evident between the mammalian and fish leptin system. Thus, for instance, mammalian leptin is synthesized and released by the adipose tissue in response to the amount of fat depots, while several tissues (mainly the liver) are the main sources of leptin in fish, whose determining factors of production are still unclear. In mammals, the main physiological role for leptin is its involvement in the maintenance of energy balance by decreasing food intake and increasing energy expenditure, although a wide variety of actions have been attributed to this hormone (e.g., regulation of lipid and carbohydrate metabolism, reproduction and immune functions). In fish, available literature also points towards a multifunctional nature for leptin, although knowledge on its functions is limited. In this review, we offer an overview of teleostean leptin structure and mechanism of action, and discuss the available knowledge on the role of this hormone in food intake regulation in teleost fish, aiming to provide a comparative overview between the functioning of the teleostean and mammalian leptin systems.
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Affiliation(s)
- Ayelén Melisa Blanco
- Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía and Centro de Investigación Mariña, Universidade de Vigo, Vigo, Pontevedra, Spain
| | - José Luis Soengas
- Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía and Centro de Investigación Mariña, Universidade de Vigo, Vigo, Pontevedra, Spain.
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23
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Erkasap N, Ozyurt R, Ozkurt M, Erkasap S, Yasar F, Ihtiyar E, Ciftci E, Canaz F, Colak E. Role of Notch, IL-1 and leptin expression in colorectal cancer. Exp Ther Med 2021; 21:600. [PMID: 33884038 PMCID: PMC8056113 DOI: 10.3892/etm.2021.10032] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/11/2021] [Indexed: 11/10/2022] Open
Abstract
An increasing number of studies have shown that angiogenesis has an important role in the progression of cancer. The growth of a new network of blood vessels is crucial for tumor growth and metastasis, which is promoted by several proangiogenic factors. Leptin, an essential adipokine that is secreted from fat tissue, is one of these pro-angiogenic factors. It has been shown that the inhibition of leptin-induced angiogenesis resulted in decreased levels of vascular endothelial growth factor (VEGF)/VEGFR2, hypoxia inducible factor (HIF) 1α, NF-κB, IL-1 and Notch and reduced the tumor growth in breast cancer. Leptin induces angiogenesis in breast cancer either by upregulating VEGFR2 in endothelial cells or by increasing VEGF/VEGFR2 expression through the Notch, IL-1 and leptin crosstalk outcome (NILCO) pathway. NILCO is a novel mechanism that interacts with proinflammatory and proangiogenic signals, which are critical for cell proliferation and angiogenesis in cancer. Several studies have shown that components of NILCO may affect human cancer incidence and progression. However, to the best of our knowledge, the interactions between Notch, IL-1 and leptin in human colorectal cancer have not been yet studied at the molecular level. The aim of the present study was to investigate the expression levels of genes related to the NILCO pathway in human colorectal cancer specimens. The current results demonstrated that leptin, leptin receptor (ObR) b, Notch-1, Notch-4, IL-1α, IL-1β, IL-1R, IL-6, JAK-2, STAT-1, STAT-3, VEGFA, VEGFR1, VEGFR2, TNF-α and NF-κB mRNA expression levels in the cancer tissue were increased compared with the normal tissue. No significant changes in the mRNA expression levels of Jagged-1, HIF-1α and TNF receptor 1 were observed. Western blotting revealed that the protein expression levels of IκB were increased in the cancer tissue compared with normal tissue, whereas HIF-1α and phosphorylated STAT-1 levels were decreased. IL-6 and VEGFA plasma concentrations were statistically raised and the leptin plasma concentration was also raised, although significantly, patients with cancer compared with control individuals. Together, the present findings indicated that Notch, IL-1 and leptin may serve a crucial role in the development of colorectal cancer.
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Affiliation(s)
- Nilufer Erkasap
- Department of Physiology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Rumeysa Ozyurt
- Department of Physiology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Mete Ozkurt
- Department of Physiology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Serdar Erkasap
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Fatih Yasar
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Enver Ihtiyar
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Evrim Ciftci
- Department of Pathology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Funda Canaz
- Department of Pathology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Ertugrul Colak
- Department of Biostatistics, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
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Kietzmann T, Mäkelä VH. The hypoxia response and nutritional peptides. Peptides 2021; 138:170507. [PMID: 33577839 DOI: 10.1016/j.peptides.2021.170507] [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: 12/15/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 10/22/2022]
Abstract
Hypoxia controls metabolism at several levels, e.g., via mitochondrial ATP production, glucose uptake and glycolysis. Hence it is likely that hypoxia also affects the action and/or production of many peptide hormones linked to food intake and appetite control. Many of those are produced in the gastrointestinal tract, endocrine pancreas, adipose tissue, and selective areas in the brain which modulate and concert their actions. However, the complexity of the hypoxia response and the links to peptides/hormones involved in food intake and appetite control in the different organs are not well known. This review summarizes the role of the hypoxia response and its effects on major peptides linked to appetite regulation, nutrition and metabolism.
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Affiliation(s)
- Thomas Kietzmann
- University of Oulu, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Oulu, Finland.
| | - Ville H Mäkelä
- University of Oulu, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Oulu, Finland
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25
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Annett S, Moore G, Robson T. Obesity and Cancer Metastasis: Molecular and Translational Perspectives. Cancers (Basel) 2020; 12:E3798. [PMID: 33339340 PMCID: PMC7766668 DOI: 10.3390/cancers12123798] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is a modern health problem that has reached pandemic proportions. It is an established risk factor for carcinogenesis, however, evidence for the contribution of adipose tissue to the metastatic behavior of tumors is also mounting. Over 90% of cancer mortality is attributed to metastasis and metastatic tumor cells must communicate with their microenvironment for survival. Many of the characteristics observed in obese adipose tissue strongly mirror the tumor microenvironment. Thus in the case of prostate, pancreatic and breast cancer and esophageal adenocarcinoma, which are all located in close anatomical proximity to an adipose tissue depot, the adjacent fat provides an ideal microenvironment to enhance tumor growth, progression and metastasis. Adipocytes provide adipokines, fatty acids and other soluble factors to tumor cells whilst immune cells infiltrate the tumor microenvironment. In addition, there are emerging studies on the role of the extracellular vesicles secreted from adipose tissue, and the extracellular matrix itself, as drivers of obesity-induced metastasis. In the present review, we discuss the major mechanisms responsible for the obesity-metastatic link. Furthermore, understanding these complex mechanisms will provide novel therapies to halt the tumor-adipose tissue crosstalk with the ultimate aim of inhibiting tumor progression and metastatic growth.
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Affiliation(s)
| | | | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Science, 123 St Stephen’s Green, Dublin D02 YN77, Ireland; (S.A.); (G.M.)
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Zhang J, Ma J, Zhou X, Hu S, Ge L, Sun J, Li P, Long K, Jin L, Tang Q, Liu L, Li X, Shuai S, Li M. Comprehensive Analysis of mRNA and lncRNA Transcriptomes Reveals the Differentially Hypoxic Response of Preadipocytes During Adipogenesis. Front Genet 2020; 11:845. [PMID: 32849828 PMCID: PMC7425071 DOI: 10.3389/fgene.2020.00845] [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: 05/03/2020] [Accepted: 07/13/2020] [Indexed: 11/28/2022] Open
Abstract
Local hypoxia has recently been reported to occur in the white adipose tissue (WAT) microenvironment during obesity. Adipocytes have a unique life cycle that reflects the different stages of adipogenesis in the WAT niche. Long non-coding RNAs (lncRNAs) play an important role in the cellular response to hypoxia. However, the differentially hypoxic responses of preadipocytes during adipogenesis and the potential role of lncRNAs in this process remain to be elucidated. Here, we evaluated the differentially hypoxic responses of primary hamster preadipocytes during adipogenesis and analyzed mRNA and lncRNA expression in same Ribo-Zero RNA-seq libraries. Hypoxia induced HIF-1α protein during adipogenesis and caused divergent changes of cell phenotypes. A total of 10,318 mRNAs were identified to be expressed in twenty libraries (five timepoints), and 3,198 differentially expressed mRNAs (DE mRNAs) were detected at five timepoints (hypoxia vs. normoxia). Functional enrichment analysis revealed the shared and specific hypoxia response pathways in the different stages of adipogenesis. Hypoxia differentially modulated the expression profile of adipose-associated genes, including adipokines, lipogenesis, lipolysis, hyperplasia, hypertrophy, inflammatory, and extracellular matrix. We also identified 4,296 lncRNAs that were expressed substantially and detected 1,431 DE lncRNAs at five timepoints. Two, 3, 5, 13, and 50 DE mRNAs at D0, D1, D3, D7, and D11, respectively, were highly correlated and locus-nearby DE lncRNAs and mainly involved in the cell cycle, vesicle-mediated transport, and mitochondrion organization. We identified 28 one-to-one lncRNA-mRNA pairs that might be closely related to adipocyte functions, such as ENSCGRT00015041780-Hilpda, TU2105-Cdsn, and TU17588-Ltbp3. These lncRNAs may represent the crucial regulation axis in the cellular response to hypoxia during adipogenesis. This study dissected the effects of hypoxia in the cell during adipogenesis, uncovered novel regulators potentially associated with WAT function, and may provide a new viewpoint for interpretation and treatment of obesity.
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Affiliation(s)
- Jinwei Zhang
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Jideng Ma
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xiankun Zhou
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Silu Hu
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Liangpeng Ge
- Chongqing Academy of Animal Sciences, Chongqing, China.,Key Laboratory of Pig Industry Sciences, Ministry of Agriculture, Chongqing, China.,Chongqing Key Laboratory of Pig Industry Sciences, Chongqing, China
| | - Jing Sun
- Chongqing Academy of Animal Sciences, Chongqing, China.,Key Laboratory of Pig Industry Sciences, Ministry of Agriculture, Chongqing, China.,Chongqing Key Laboratory of Pig Industry Sciences, Chongqing, China
| | - Penghao Li
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Xi Nan Gynecological Hospital, Chengdu, China
| | - Keren Long
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Long Jin
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Qianzi Tang
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Lingyan Liu
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xuewei Li
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Surong Shuai
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Mingzhou Li
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
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27
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Gauda EB, Conde S, Bassi M, Zoccal DB, Almeida Colombari DS, Colombari E, Despotovic N. Leptin: Master Regulator of Biological Functions that Affects Breathing. Compr Physiol 2020; 10:1047-1083. [PMID: 32941688 DOI: 10.1002/cphy.c190031] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Obesity is a global epidemic in developed countries accounting for many of the metabolic and cardiorespiratory morbidities that occur in adults. These morbidities include type 2 diabetes, sleep-disordered breathing (SDB), obstructive sleep apnea, chronic intermittent hypoxia, and hypertension. Leptin, produced by adipocytes, is a master regulator of metabolism and of many other biological functions including central and peripheral circuits that control breathing. By binding to receptors on cells and neurons in the brainstem, hypothalamus, and carotid body, leptin links energy and metabolism to breathing. In this comprehensive article, we review the central and peripheral locations of leptin's actions that affect cardiorespiratory responses during health and disease, with a particular focus on obesity, SDB, and its effects during early development. Obesity-induced hyperleptinemia is associated with centrally mediated hypoventilation with decrease CO2 sensitivity. On the other hand, hyperleptinemia augments peripheral chemoreflexes to hypoxia and induces sympathoexcitation. Thus, "leptin resistance" in obesity is relative. We delineate the circuits responsible for these divergent effects, including signaling pathways. We review the unique effects of leptin during development on organogenesis, feeding behavior, and cardiorespiratory responses, and how undernutrition and overnutrition during critical periods of development can lead to cardiorespiratory comorbidities in adulthood. We conclude with suggestions for future directions to improve our understanding of leptin dysregulation and associated clinical diseases and possible therapeutic targets. Lastly, we briefly discuss the yin and the yang, specifically the contribution of relative adiponectin deficiency in adults with hyperleptinemia to the development of metabolic and cardiovascular disease. © 2020 American Physiological Society. Compr Physiol 10:1047-1083, 2020.
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Affiliation(s)
- Estelle B Gauda
- Division of Neonatology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Silvia Conde
- CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Lisboa, Portugal
| | - Mirian Bassi
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | - Daniel B Zoccal
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | - Debora Simoes Almeida Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | - Eduardo Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
| | - Nikola Despotovic
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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28
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Emara TA, Khazbak AO, Mohammed O, Elgaml M, Zidan A, Hosny SM. Changes in Serum Leptin Level After Multilevel Surgery in Patients with Obstructive Sleep Apnea. Laryngoscope 2020; 131:E665-E670. [PMID: 32640082 DOI: 10.1002/lary.28908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 06/08/2020] [Accepted: 06/15/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Leptin hormone plays an important role in metabolic control and is elevated in obstructive sleep apnea (OSA). The aim of this study was to assess the hypothesis that surgical treatment will reduce leptin levels in OSA patients. STUDY DESIGN Prospective study. SUBJECTS AND METHODS Twenty-three patients with multilevel OSA underwent modified genioglossus muscle advancement with anterolateral advancement pharyngoplasty between April 2018 and September 2019. Serum leptin level was measured preoperatively and 3 months postoperatively for all patients and 18 control subjects. All patients were evaluated before and 3 months after surgery by history taking, clinical examination, polysomnography, cephalometry, and Epworth Sleepiness Scale. RESULTS Preoperatively, patients with OSA had a higher Leptin level (18.46 ± 4.73 ng/mL) than did control subjects (7.07 ± 1.26 ng/mL) (P < .001). Surgery resulted in a significant reduction in the level of leptin from 18.46 ± 4.73 ng/mL to 8.03 ± 2.22 ng/mL (P < .001). Reductions in leptin level was correlated with changes in apnea hypopnea index (AHI) (r = 0.61, P = .002) and minimum oxygen saturation (SaO2) (r = -0.54, P = .008). CONCLUSION Effective multilevel surgery in the form of modified genioglossus muscle advancement with anterolateral advancement pharyngoplasty could significantly reduce leptin level in OSA patients and this reduction is correlated with the degree of OSA improvement in term of AHI and SaO2. LEVEL OF EVIDENCE 4 Laryngoscope, 131:E665-E670, 2021.
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Affiliation(s)
- Tarek A Emara
- Otorhinolaryngology-Head & Neck Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Alaa O Khazbak
- Otorhinolaryngology-Head & Neck Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Omnya Mohammed
- Otorhinolaryngology-Head & Neck Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mohamed Elgaml
- Otorhinolaryngology-Head & Neck Surgery Department, Al Ahrar Teaching Hospital, Zagazig, Egypt
| | - Amal Zidan
- Clinical Pathology Department, Zagazig University, Zagazig, Egypt
| | - Sameh M Hosny
- Otorhinolaryngology-Head & Neck Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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CXCL13 is a differentiation- and hypoxia-induced adipocytokine that exacerbates the inflammatory phenotype of adipocytes through PHLPP1 induction. Biochem J 2020; 476:3533-3548. [PMID: 31710352 DOI: 10.1042/bcj20190709] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/04/2019] [Accepted: 11/11/2019] [Indexed: 01/16/2023]
Abstract
Hypoxia in adipose tissue is regarded as a trigger that induces dysregulation of the secretory profile in adipocytes. Similarly, local dysregulation of adipocytokine secretion is an initial event in the deleterious effects of obesity on metabolism. We previously reported that CXCL13 is highly produced during adipogenesis, however little is known about the roles of CXCL13 in adipocytes. Here, we found that hypoxia, as modeled by 1% O2 or exposure to the hypoxia-mimetic reagent desferrioxamine (DFO) has strong inductive effects on the expression of CXCL13 and CXCR5, a CXCL13 receptor, in both undifferentiated and differentiated adipocytes and in organ-cultured white adipose tissue (WAT). CXCL13 was also highly expressed in WAT from high fat diet-fed mice. Hypoxic profile, typified by increased expression of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) and decreased expression of adiponectin, was significantly induced by CXCL13 treatment during adipogenic differentiation. Conversely, the treatment of adipocytes with a neutralizing-antibody against CXCL13 as well as CXCR5 knockdown by specific siRNA effectively inhibited DFO-induced inflammation. The phosphorylation of Akt2, a protective factor of adipose inflammation, was significantly inhibited by CXCL13 treatment during adipogenic differentiation. Mechanistically, CXCL13 induces the expression of PHLPP1, an Akt2 phosphatase, through focal adhesion kinase (FAK) signaling; and correspondingly we show that CXCL13 and DFO-induced IL-6 and PAI-1 expression was blocked by Phlpp1 knockdown. Furthermore, we revealed the functional binding sites of PPARγ2 and HIF1-α within the Cxcl13 promoter. Taken together, these results indicate that CXCL13 is an adipocytokine that facilitates hypoxia-induced inflammation in adipocytes through FAK-mediated induction of PHLPP1 in autocrine and/or paracrine manner.
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30
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Dai H, Yuan Y, Yin S, Zhang Y, Han Y, Sun L, Li T, Xu J, Sheng L, Gong Y, Li Y. Metoprolol Inhibits Profibrotic Remodeling of Epicardial Adipose Tissue in a Canine Model of Chronic Obstructive Sleep Apnea. J Am Heart Assoc 2020; 8:e011155. [PMID: 30686096 PMCID: PMC6405574 DOI: 10.1161/jaha.118.011155] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Whether chronic obstructive sleep apnea ( OSA ) could promote epicardial adipose tissue ( EAT ) secretion of profibrotic adipokines, and thereby contribute to atrial fibrosis, and the potential therapeutic effects of metoprolol remain unknown. Methods and Results A chronic OSA canine model was established by repeatedly clamping the endotracheal tube for and then reopening it for 4 hours every other day for 12 weeks. In a metoprolol treatment group, metoprolol succinate was administered daily for 12 weeks. The EAT infiltration and left atrial fibrosis were examined. The expressions of adipokines secreted by EAT and hypoxic 3T3-L1 adipocytes were detected. The changes in collagen synthesis, transforming growth factor-β1 expression, and cell differentiation and proliferation in cardiac fibroblasts induced by hypoxic 3T3-L1 adipocyte-derived conditioned medium were further analyzed. Chronic OSA induced infiltration of EAT into the left atrium. OSA enhanced the profibrotic effect of EAT on the adjacent atrial myocardium. Moreover, OSA induced profibrotic cytokine secretion from EAT . We also found that hypoxia induced adipokine secretion in cultured adipocytes, and the medium conditioned by the hypoxic adipocytes increased collagen and transforming growth factor-β1 protein expression and cell proliferation of cardiac fibroblasts. More importantly, metoprolol attenuated infiltration of EAT and alleviated the profibrotic effect of EAT by inhibiting adipokine secretion. Metoprolol also inhibited hypoxia-induced adipokine secretion in adipocytes and thereby blocked the hypoxic adipocyte-derived conditioned medium-induced fibrotic response of cardiac fibroblasts. Conclusions Chronic OSA enhanced the profibrotic effect of EAT on the neighboring atrial myocardium by stimulating the secretion of profibrotic adipokines from EAT , which was significantly attenuated by metoprolol. This study gives insights into mechanisms underlying OSA -induced atrial fibrillation and also provides experimental evidence for the protective effects of metoprolol.
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Affiliation(s)
- Hui Dai
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China.,2 Department of Emergency Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Yue Yuan
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Shuangli Yin
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Yun Zhang
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Yu Han
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Li Sun
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Tiankai Li
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Jicheng Xu
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Li Sheng
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Yongtai Gong
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
| | - Yue Li
- 1 Department of Cardiology the First Affiliated Hospital Harbin Medical University Harbin China
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Musutova M, Weiszenstein M, Koc M, Polak J. Intermittent Hypoxia Stimulates Lipolysis, But Inhibits Differentiation and De Novo Lipogenesis in 3T3-L1 Cells. Metab Syndr Relat Disord 2020; 18:146-153. [PMID: 31928504 DOI: 10.1089/met.2019.0112] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: Exposure to intermittent hypoxia (IH) may play a role in the development of metabolic impairments in the context of obstructive sleep apnea syndrome, probably by elevated plasma levels of free fatty acids. Employing gas-permeable cultureware to grow differentiated human and mouse adipocytes in vitro, we directly studied the effects of pericellular oxygen fluctuations on key adipocyte metabolic functions-spontaneous lipolytic rates, triglyceride accumulation, de novo lipogenesis, and expression of adipocyte-specific marker genes. Materials and Methods: 3T3-L1 fibroblasts and human subcutaneous preadipocytes were differentiated under conditions that induced repetitive pericellular-oxygen cycles IH between 1% O2 (5 min) and 16% O2 (5 min), continuously for 14 days or under control conditions. Chemicals were used to inhibit the flux of acetyl-CoA from glycolysis (alfa-cyano-4-hydroxy cinnamate) or the tricarboxylic acid cycle (SB204990), or to stimulate the flux of acetyl-CoA from pyruvate to the lipogenic pool. Lipolytic rate, intracellular lipids, and expression of adipocyte differentiation markers were assessed and t-test or ANOVA were used to find significant differences. Results: The rate of lipolysis increased by 211% in 3T3-L1 cells and by 39% in obese human adipocytes. Exposure to IH reduced intracellular lipid stores by 37% and reduced the expression of adipocyte differentiation markers. Pharmacological stimulation or inhibition of de novo lipogenesis did not modify the intracellular lipid content under IH. Conclusions: Pericellular oxygen fluctuations directly stimulated lipolysis, but did not increase de novo lipogenesis from endogenous substrates. Similarly, IH hampered adipocyte differentiation from precursors.
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Affiliation(s)
- Martina Musutova
- Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.,Faculty of Science, Charles University, Prague, Czech Republic
| | - Martin Weiszenstein
- Unit for Chemical Safety, Centre of Industrial Hygiene and Occupational Health, National Institute of Public Health, Prague, Czech Republic
| | - Michal Koc
- Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Polak
- Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Abstract
Leptin is a hormone that plays a major role as mediator of long-term regulation of energy balance, suppressing food intake, and stimulating weight loss. More recently, important physiological roles other than controlling appetite and energy expenditure have been suggested for leptin, including neuroendocrine, reparative, reproductive, and immune functions. These emerging peripheral roles let hypothesize that leptin can modulate also cancer progression. Indeed, many studies have demonstrated that elevated chronic serum concentrations of leptin, frequently seen in obese subjects, represent a stimulatory signal for tumor growth. Current knowledge indicates that also different non-tumoral cells resident in tumor microenvironment may respond to leptin creating a favorable soil for cancer cells. In addition, leptin is produced also within the tumor microenvironment creating the possibility for paracrine and autocrine action. In this review, we describe the main mechanisms that regulate peripheral leptin availability and how leptin can shape tumor microenvironment.
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Lempesis IG, Meijel RLJ, Manolopoulos KN, Goossens GH. Oxygenation of adipose tissue: A human perspective. Acta Physiol (Oxf) 2020; 228:e13298. [PMID: 31077538 PMCID: PMC6916558 DOI: 10.1111/apha.13298] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/03/2019] [Accepted: 05/08/2019] [Indexed: 12/13/2022]
Abstract
Obesity is a complex disorder of excessive adiposity, and is associated with adverse health effects such as cardiometabolic complications, which are to a large extent attributable to dysfunctional white adipose tissue. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, impaired adipokine secretion, a chronic low‐grade inflammatory status, hormonal resistance and altered metabolic responses, together contributing to insulin resistance and related chronic diseases. Adipose tissue hypoxia, defined as a relative oxygen deficit, in obesity has been proposed as a potential contributor to adipose tissue dysfunction, but studies in humans have yielded conflicting results. Here, we will review the role of adipose tissue oxygenation in the pathophysiology of obesity‐related complications, with a specific focus on human studies. We will provide an overview of the determinants of adipose tissue oxygenation, as well as the role of adipose tissue oxygenation in glucose homeostasis, lipid metabolism and inflammation. Finally, we will discuss the putative effects of physiological and experimental hypoxia on adipose tissue biology and whole‐body metabolism in humans. We conclude that several lines of evidence suggest that alteration of adipose tissue oxygenation may impact metabolic homeostasis, thereby providing a novel strategy to combat chronic metabolic diseases in obese humans.
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Affiliation(s)
- Ioannis G. Lempesis
- College of Medical and Dental Sciences, Institute of Metabolism and Systems Research (IMSR) University of Birmingham Birmingham UK
- Centre for Endocrinology, Diabetes and Metabolism Birmingham Health Partners Birmingham UK
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University Medical Centre Maastricht the Netherlands
| | - Rens L. J. Meijel
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University Medical Centre Maastricht the Netherlands
| | - Konstantinos N. Manolopoulos
- College of Medical and Dental Sciences, Institute of Metabolism and Systems Research (IMSR) University of Birmingham Birmingham UK
- Centre for Endocrinology, Diabetes and Metabolism Birmingham Health Partners Birmingham UK
| | - Gijs H. Goossens
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University Medical Centre Maastricht the Netherlands
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Janjić K, Schellner A, Engenhart A, Kernstock K, Schädl B, Moritz A, Agis H. Angiopoietin-like 4 production upon treatment with hypoxia and L-mimosine in periodontal fibroblasts. J Periodontal Res 2019; 54:489-498. [PMID: 30891777 PMCID: PMC6790701 DOI: 10.1111/jre.12649] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 01/30/2019] [Accepted: 02/11/2019] [Indexed: 12/22/2022]
Abstract
Background and objective A key factor in the modulation of angiogenesis as well as in bone resorption is angiopoietin‐like 4. However, the role of angiopoietin‐like 4 in periodontal tissue is unknown. Here, we hypothesized that hypoxia and the hypoxia mimetic agent L‐mimosine can induce the production of angiopoietin‐like 4 in periodontal fibroblasts. Methods Human periodontal ligament fibroblasts (PDLF) were cultured in monolayer and spheroid cultures. The cultures were incubated in the presence of hypoxia or L‐mimosine. Angiopoietin‐like 4 mRNA and protein levels were measured by qPCR and ELISA, respectively. Also, the impact of Lipopolysaccharides of E. coli and P. gingivalis, interleukin (IL)‐1β and tumor necrosis factor (TNF)α was evaluated. Furthermore, we tested dependency on hypoxia‐inducible factor (HIF)‐1 activity by Western blotting for HIF‐1 and inhibitor studies with echinomycin. Potential autocrine effects were assessed by exposure of PDLF to recombinant angiopoietin‐like 4 in full length, C‐terminal and N‐terminal fragments. The impact on viability, DNA synthesis, alkaline phosphatase, and matrix mineralization was evaluated. Results Both hypoxia and L‐mimosine elevated angiopoietin‐like 4 mRNA and protein levels in monolayer cultures of PDLF. HIF‐1 was elevated after both hypoxia and L‐mimosine treatment. LPS, IL‐1β, and TNFα did not modulate angiopoietin‐like 4 levels significantly. Addition of echinomycin in the cultures inhibited the production of angiopoietin‐like 4. In spheroid cultures of PDLF, the increase did not reach the level of significance at mRNA and protein levels. Angiopoietin‐like 4 in full length, C‐terminal, and N‐terminal fragments did not modulate viability, DNA synthesis, alkaline phosphatase, and matrix mineralization. Conclusion Overall, we found that hypoxia and the hypoxia mimetic agent L‐mimosine can stimulate angiopoietin‐like 4 production in monolayer cultures of PDLF. This increase depends on HIF‐1 activity. Future studies will reveal how the modulation of angiopoietin‐like 4 in the periodontium contributes to periodontal disease and regeneration.
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Affiliation(s)
- Klara Janjić
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Alwina Schellner
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Alexander Engenhart
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Kurt Kernstock
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Barbara Schädl
- Austrian Cluster for Tissue Regeneration, Vienna, Austria.,Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Andreas Moritz
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Hermann Agis
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
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Abstract
Gaseous oxygen is essential for all aerobic animals, without which mitochondrial respiration and oxidative phosphorylation cannot take place. It is not, however, regarded as a "nutrient" by nutritionists and does not feature as such within the discipline of nutritional science. This is primarily a consequence of the route by which O2 enters the body, which is via the nose and lungs in terrestrial animals as opposed to the mouth and gastrointestinal tract for what are customarily considered as nutrients. It is argued that the route of entry should not be the critical factor in defining whether a substance is, or is not, a nutrient. Indeed, O2 unambiguously meets the standard dictionary definitions of a nutrient, such as "a substance that provides nourishment for the maintenance of life and for growth" (Oxford English Dictionary). O2 is generally available in abundance, but deficiency occurs at high altitude and during deep sea dives, as well as in lung diseases. These impact on the provision at a whole-body level, but a low pO2 is characteristic of specific tissues includings the retina and brain, while deficiency, or overt hypoxia, is evident in certain conditions such as ischaemic disease and in tumours - and in white adipose tissue in obesity. Hypoxia results in a switch from oxidative metabolism to increased glucose utilisation through anaerobic glycolysis, and there are extensive changes in the expression of multiple genes in O2-deficient cells. These changes are driven by hypoxia-sensitive transcription factors, particularly hypoxia-inducible factor-1 (HIF-1). O2 deficiency at a whole-body level can be treated by therapy or supplementation, but O2 is also toxic through the generation of reactive oxygen species. It is concluded that O2 is a critical, but overlooked, nutrient which should be considered as part of the landscape of nutritional science.
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Affiliation(s)
- Paul Trayhurn
- Clore Laboratory, University of Buckingham, Buckingham, United Kingdom.,Obesity Biology Unit, University of Liverpool, Liverpool, United Kingdom
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Pan W, Liu C, Zhang J, Gao X, Yu S, Tan H, Yu J, Qian D, Li J, Bian S, Yang J, Zhang C, Huang L, Jin J. Association Between Single Nucleotide Polymorphisms in PPARA and EPAS1 Genes and High-Altitude Appetite Loss in Chinese Young Men. Front Physiol 2019; 10:59. [PMID: 30778304 PMCID: PMC6369186 DOI: 10.3389/fphys.2019.00059] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/18/2019] [Indexed: 12/24/2022] Open
Abstract
Appetite loss is a common symptom that occurs in high altitude (HA) for lowlanders. Previous studies indicated that hypoxia is the initiating vital factor of HA appetite loss. PPARA, EPAS1, EGLN1, HIF1A, HIF1AN, and NFE2L2 play important roles in hypoxic responses. We aimed to explore the association of these hypoxia-related gene polymorphisms with HA appetite loss. In this study, we enrolled 416 young men who rapidly ascended to Lhasa (3700 m) from Chengdu (<500m) by plane. PPARA, EPAS1, EGLN1, HIF1A, HIF1AN, and NFE2L2 were genotyped by MassARRAY. Appetite scores were measured to identify HA appetite loss. Logistic regression and multiple genetic models were tested to evaluate the association between the single nucleotide polymorphisms (SNPs) and risk of HA appetite loss in crude and adjusted (age and SaO2) analysis. Subsequently, Haploview software was used to analyze the linkage disequilibrium (LD), haplotype construction and the association of diverse haplotypes with the risk of HA appetite loss. Our results revealed that allele “A” in PPARA rs4253747 was significantly associated with the increased risk of HA appetite loss. Codominant, dominant, recessive, and log-additive models of PPARA rs4253747 showed the increased risk of HA appetite loss in the crude and adjusted analysis. However, only dominant, overdominant, and log-additive models of EPAS1 rs6756667 showed decreased risk of HA appetite loss in the crude and adjusted analysis. Moreover, the results from haplotype-based test showed that the rs7292407-rs6520015 haplotype “AC” was associated with HA appetite loss in the crude analysis rather than the adjusted analysis. In this study, we first established the association of SNPs in PPARA (rs4253747) and EPAS1 (rs6756667) genes with susceptibility to HA appetite loss in Han Chinese young men. These findings provide novel insights into understanding the mechanisms involved in HA appetite loss.
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Affiliation(s)
- Wenxu Pan
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Chuan Liu
- Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Jihang Zhang
- Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Xubin Gao
- Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Shiyong Yu
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Hu Tan
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Jie Yu
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Dehui Qian
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Jiabei Li
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Shizhu Bian
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Jie Yang
- Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Chen Zhang
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Lan Huang
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Jun Jin
- Department of Cardiology, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China.,Institute of Cardiovascular Diseases, Xinqiao Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
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Hughes MF, Lenighan YM, Godson C, Roche HM. Exploring Coronary Artery Disease GWAs Targets With Functional Links to Immunometabolism. Front Cardiovasc Med 2018; 5:148. [PMID: 30460244 PMCID: PMC6232936 DOI: 10.3389/fcvm.2018.00148] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 10/01/2018] [Indexed: 12/24/2022] Open
Abstract
Finding genetic variants that cause functional disruption or regulatory change among the many implicated GWAs variants remains a key challenge to translating the findings from GWAs to therapeutic treatments. Defining the causal mechanisms behind the variants require functional screening experiments that can be complex and costly. Prioritizing variants for functional characterization using techniques that capture important functional and regulatory elements can assist this. The genetic architecture of complex traits such as cardiovascular disease and type II diabetes comprise an enormously large number of variants of small effect contributing to heritability and spread throughout the genome. This makes it difficult to distinguish which variants or core genes are most relevant for prioritization and how they contribute to the regulatory networks that become dysregulated leading to disease. Despite these challenges, recent GWAs for CAD prioritized genes associated with lipid metabolism, coagulation and adhesion along with novel signals related to innate immunity, adipose tissue and, vascular function as important core drivers of risk. We focus on three examples of novel signals associated with CAD which affect risk through missense or UTR mutations indicating their potential for therapeutic modification. These variants play roles in adipose tissue function vascular function and innate immunity which form the cornerstones of immuno-metabolism. In addition we have explored the putative, but potentially important interactions between the environment, specifically food and nutrition, with respect to key processes.
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Affiliation(s)
- Maria F Hughes
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.,Nutrigenomics Research Group, UCD Institute of Food and Health, School of Public Health Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland.,Centre of Excellence for Public Health, Queen's University Belfast, Belfast, United Kingdom.,UCD Institute of Food and Health, School of Public Health Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
| | - Yvonne M Lenighan
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.,UCD Institute of Food and Health, School of Public Health Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.,School of Medicine, University College Dublin, Dublin, Ireland
| | - Helen M Roche
- UCD Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.,Nutrigenomics Research Group, UCD Institute of Food and Health, School of Public Health Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland.,UCD Institute of Food and Health, School of Public Health Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
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38
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Freitas LS, Furlan SF, Drager LF. Obstructive Sleep Apnea and Metabolic Risk: an Update. CURRENT SLEEP MEDICINE REPORTS 2018. [DOI: 10.1007/s40675-018-0118-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Chylikova J, Dvorackova J, Tauber Z, Kamarad V. M1/M2 macrophage polarization in human obese adipose tissue. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 162:79-82. [PMID: 29765169 DOI: 10.5507/bp.2018.015] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/27/2018] [Indexed: 12/31/2022] Open
Abstract
Obesity and insulin resistance are closely associated with chronic inflammation in adipose tissue, where macrophages play an important role. Adipose tissue macrophages can be divided into two main phenotypes: the classical M1 macrophages and alternatively activated macrophages M2. M1 macrophages produce pro-inflammatory cytokines (TNF-α, interleukin IL-6 and MCP-1) and thus contribute to the development of insulin resistance. On the other hand, M2 macrophages, anti-inflammatory, are involved in the maintenance of tissue homeostasis and are typical in the adipose tissue of slender individuals. Macrophages can also play a role in the pathogenesis of other serious illnesses such as cardiovascular diseases or cancer. This article reviews the latest data on macrophage polarization in adipose tissue.
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Affiliation(s)
- Jaroslava Chylikova
- Department of Histology and Embryology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Jana Dvorackova
- Department of Pathology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Zdenek Tauber
- Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Vojtech Kamarad
- Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
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40
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Ruhl T, Storti G, Pallua N. Proliferation, Metabolic Activity, and Adipogenic Differentiation of Human Preadipocytes Exposed to 2 Surfactants In Vitro. J Pharm Sci 2018; 107:1408-1415. [DOI: 10.1016/j.xphs.2017.12.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/24/2017] [Accepted: 12/14/2017] [Indexed: 01/09/2023]
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41
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Lobanova MV, Ratushnyy AY, Ezdakova MI, Buravkova LB. The Resistance of Multipotent Mesenchymal Stromal Cells to the Effect of Glucose Deprivation under Conditions of a Reduced Oxygen Content. Biophysics (Nagoya-shi) 2018. [DOI: 10.1134/s0006350918030120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Distinct hypoxic regulation of preadipocyte factor-1 (Pref-1) in preadipocytes and mature adipocytes. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:334-342. [DOI: 10.1016/j.bbamcr.2017.11.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 10/15/2017] [Accepted: 11/10/2017] [Indexed: 01/08/2023]
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Douros JD, Baltzegar DA, Reading BJ, Seale AP, Lerner DT, Grau EG, Borski RJ. Leptin Stimulates Cellular Glycolysis Through a STAT3 Dependent Mechanism in Tilapia. Front Endocrinol (Lausanne) 2018; 9:465. [PMID: 30186233 PMCID: PMC6110908 DOI: 10.3389/fendo.2018.00465] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 07/27/2018] [Indexed: 12/18/2022] Open
Abstract
We assessed if leptin, a cytokine hormone known to enhance energy expenditure by promoting lipid and carbohydrate catabolism in response to physiologic stress, might directly regulate cellular glycolysis. A transcriptomic analysis of prolactin cells in the tilapia (Oreochromis mossambicus) pituitary rostral pars distalis (RPD) revealed that recombinant leptin (rtLep) differentially regulates 1,995 genes, in vitro. Machine learning algorithms and clustering analyses show leptin influences numerous cellular gene networks including metabolism; protein processing, transport, and metabolism; cell cycle and the hypoxia response. Leptin stimulates transcript abundance of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (gapdh) in a covariate manner to the hypoxic stress gene network. Orthogonal tests confirm that rtLepA dose-dependently increases gapdh gene expression in the RPD along with transcript abundance of 6-phosphofructo-1-kinase (pfk1), the rate limiting glycolytic enzyme. Functional testing demonstrated that leptin stimulates PFK activity and glycolytic output, while Stattic (a STAT3 blocker) was sufficient to suppress these responses, indicating leptin stimulates glycolysis through a STAT3-dependent mechanism. Leptin also stimulated pfk1 gene expression and lactate production in primary hepatocyte incubations in a similar manner to those shown for the pituitary RPD. This work characterizes a critical metabolic action of leptin to directly stimulate glycolysis across tissue types in a teleost model system, and suggest that leptin may promote energy expenditure, in part, by stimulating glycolysis. These data in a teleost fish, suggest that one of leptin's ancient, highly-conserved functions among vertebrates may be stimulation of glycolysis to facilitate the energetic needs associated with various stressors.
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Affiliation(s)
- Jonathan D. Douros
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
| | - David A. Baltzegar
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
- Genomics Sciences Laboratory, North Carolina State University, Raleigh, NC, United States
| | - Benjamin J. Reading
- Department of Applied Ecology, North Carolina State University, Raleigh, NC, United States
| | - Andre P. Seale
- Hawaii Institute of Marine Biology, University of Hawaii, Kaneohe, HI, United States
- Department of Human Nutrition, Food, and Animal Sciences, University of Hawaii at Mānoa, Honolulu, HI, United States
| | - Darren T. Lerner
- Hawaii Institute of Marine Biology, University of Hawaii, Kaneohe, HI, United States
- University of Hawaii Sea Grant College Program, Honolulu, HI, United States
| | - E. Gordon Grau
- Hawaii Institute of Marine Biology, University of Hawaii, Kaneohe, HI, United States
| | - Russell J. Borski
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
- *Correspondence: Russell J. Borski
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L-mimosine and hypoxia enhance angiopoietin-like 4 production involving hypoxia-inducible factor-1alpha: Insights from monolayer and spheroid cultures of dental pulp-derived cells and tooth slice cultures. Arch Oral Biol 2017; 85:172-177. [PMID: 29100106 DOI: 10.1016/j.archoralbio.2017.10.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 10/10/2017] [Accepted: 10/14/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Angiopoietin-like 4 (Angptl4) is an angiogenesis modulating signaling factor and as such involved in blood vessel formation but also in hard tissue resorption. Here we hypothesized that the hypoxia mimetic agent L-mimosine (L-MIM) and hypoxia stimulate the production of Angptl4 in the dental pulp. MATERIAL AND METHODS Monolayer and spheroid cultures of primary human dental pulp-derived cells (DPC) were treated with L-MIM or hypoxia. Furthermore, tooth slice cultures were performed. The production of Angptl4 was assessed at mRNA and protein levels using reverse transcription qPCR and immunoassays, respectively. To assess the involvement of hypoxia inducible factor (HIF)-1α (HIF-1signaling, inhibitor studies with echinomycin and Western Blot analysis for HIF-1α were performed in DPC monolayer cultures.(HIF-1 RESULTS: L-MIM and hypoxia increased production of Angptl4 at mRNA and protein levels in monolayer cultures of DPC. The increase of Angptl4 was paralleled by an increase of HIF-1α and inhibited by echinomycin. Angptl4 protein levels were also elevated in spheroid cultures. In tooth slice cultures, the pulp tissue expressed and released Angptl4 under normoxic and hypoxic conditions and in the presence of L-MIM. There was a trend for an increase in Angptl4 mRNA levels and a trend for a decrease in the protein levels of the supernatants. CONCLUSIONS Our results suggest that the hypoxia mimetic agent L-MIM and hypoxia can increase Angptl4 production in DPC involving HIF-1α. However, the increase in the cell culture supernatants does not translate in an increased release in tooth slice organ cultures.
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Ekambaram P, Parasuraman P. Differential expression of sirtuin 2 and adipocyte maturation restriction: an adaptation process during hypoxia in fish. Biol Open 2017; 6:1375-1382. [PMID: 28808139 PMCID: PMC5612243 DOI: 10.1242/bio.027334] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Sirtuins have received widespread attention due to their diverse physiological role in metabolism. Among sirtuins, SIRT2 is more abundant in adipocytes and exerts effects on adipocyte differentiation, a process which involves conversion of preadipocytes to mature adipocytes orchestrated by adipokines and adipogenic transcription factors. Grey mullet (Mugil cephalus) was chosen as a study organism due to its excellent service as a biomonitor. Adipocytes isolated from natural field conditions were termed as field-hypoxic (Ennore) and -normoxic (Kovalam) based on dissolved oxygen (DO) level in the estuary. A previous study portrayed the hypoxic instance of Ennore estuary (low DO) and grey mullet [HIF1α in adipocytes, brain endothelial cell (EC) and hepatocytes] inhabiting this estuary (
Padmini et al., 2016a,
b; Padmini and Tharani, 2015). In this context, fish adipocytes of both conditions were subjected to in vitro hypoxia for 1 h (in the pre/trigassed incubator with the supply of 1% O2; 94% N2; 5% CO2) and were analysed for the expression of adipokines, adipogenic transcription factors and anti-adipogenic markers in fish adipocytes. Elevation of asymmetric dimethylarginine (ADMA), TNFα and leptin along with decreased adiponectin, adipogenic transcription factors and altering sirtuins were observed in test adipocytes and in control adipocytes on in vitro hypoxia. This suggests that adipocytes may follow internal caloric restriction as portrayed from cytomorphological/ultrastructural analysis, limiting adipocyte maturation process, one of the adaptive mechanisms triggered by adipocyte of fish surviving in Ennore estuary. Prolonged exposure to hypoxia (test on in vitro hypoxia for 1 h) showed a drastic alteration in these components leading to both structural and biological fluctuation when compared to limited hypoxic condition (field-hypoxic and control on in vitro hypoxia). Our study concludes that hypoxia may serve as the chief molecular cue in eliciting adipocyte maturation restriction though metabolic reprogramming and it also shows the significance of adipocyte maturation restriction in imparting survival mechanism. Summary: Adipocyte maturation restriction is tightly regulated by SIRT2 activation which downregulates preadipocytes from the maturation process as adaptation strategy in fish surviving in the polluted (hypoxic) environment.
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Affiliation(s)
- Padmini Ekambaram
- P.G. Department of Biochemistry, Bharathi Women's College, Affiliated to University of Madras, Tamil Nadu, Chennai-600 108, India
| | - Parimala Parasuraman
- P.G. Department of Biochemistry, Bharathi Women's College, Affiliated to University of Madras, Tamil Nadu, Chennai-600 108, India
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Picon‐Ruiz M, Morata‐Tarifa C, Valle‐Goffin JJ, Friedman ER, Slingerland JM. Obesity and adverse breast cancer risk and outcome: Mechanistic insights and strategies for intervention. CA Cancer J Clin 2017; 67:378-397. [PMID: 28763097 PMCID: PMC5591063 DOI: 10.3322/caac.21405] [Citation(s) in RCA: 571] [Impact Index Per Article: 71.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/07/2017] [Accepted: 06/07/2017] [Indexed: 02/06/2023] Open
Abstract
Answer questions and earn CME/CNE Recent decades have seen an unprecedented rise in obesity, and the health impact thereof is increasingly evident. In 2014, worldwide, more than 1.9 billion adults were overweight (body mass index [BMI], 25-29.9 kg/m2 ), and of these, over 600 million were obese (BMI ≥30 kg/m2 ). Although the association between obesity and the risk of diabetes and coronary artery disease is widely known, the impact of obesity on cancer incidence, morbidity, and mortality is not fully appreciated. Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. The first part of this review summarizes the relationships between obesity and breast cancer development and outcomes in premenopausal and postmenopausal women and in those with hormone receptor-positive and -negative disease. The second part of this review addresses hypothesized molecular mechanistic insights that may underlie the effects of obesity to increase local and circulating proinflammatory cytokines, promote tumor angiogenesis and stimulate the most malignant cancer stem cell population to drive cancer growth, invasion, and metastasis. Finally, a review of observational studies demonstrates that increased physical activity is associated with lower breast cancer risk and better outcomes. The effects of recent lifestyle interventions to decrease sex steroids, insulin/insulin-like growth factor-1 pathway activation, and inflammatory biomarkers associated with worse breast cancer outcomes in obesity also are discussed. Although many observational studies indicate that exercise with weight loss is associated with improved breast cancer outcome, further prospective studies are needed to determine whether weight reduction will lead to improved patient outcomes. It is hoped that several ongoing lifestyle intervention trials, which are reviewed herein, will support the systematic incorporation of weight loss intervention strategies into care for patients with breast cancer. CA Cancer J Clin 2017;67:378-397. © 2017 American Cancer Society.
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Affiliation(s)
- Manuel Picon‐Ruiz
- Postdoctoral Associate, Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiFL
| | - Cynthia Morata‐Tarifa
- Postdoctoral Associate, Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiFL
| | | | - Eitan R. Friedman
- Resident in Internal Medicine, Department of MedicineUniversity of MiamiMiamiFL
| | - Joyce M. Slingerland
- Director, Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiFL
- Professor, Division of Medical Oncology, Department of MedicineDivision of Hematology Oncology, University of MiamiMiamiFL
- Professor, Department of Biochemistry and Molecular BiologyUniversity of Miami Miller School of MedicineMiamiFL.
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Ralston JC, Lyons CL, Kennedy EB, Kirwan AM, Roche HM. Fatty Acids and NLRP3 Inflammasome-Mediated Inflammation in Metabolic Tissues. Annu Rev Nutr 2017; 37:77-102. [PMID: 28826373 DOI: 10.1146/annurev-nutr-071816-064836] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Worldwide obesity rates have reached epidemic proportions and significantly contribute to the growing prevalence of metabolic diseases. Chronic low-grade inflammation, a hallmark of obesity, involves immune cell infiltration into expanding adipose tissue. In turn, obesity-associated inflammation can lead to complications in other metabolic tissues (e.g., liver, skeletal muscle, pancreas) through lipotoxicity and inflammatory signaling networks. Importantly, although numerous signaling pathways are known to integrate metabolic and inflammatory processes, the nucleotide-binding and oligomerization domain-like receptor, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome is now noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome can be influenced by various metabolites, including fatty acids. Specifically, although saturated fatty acids may promote NLRP3 inflammasome activation, monounsaturated fatty acids and polyunsaturated fatty acids have recently been shown to impede NLRP3 activity. Therefore, the NLRP3 inflammasome and associated metabolic inflammation have key roles in the relationships among fatty acids, metabolites, and metabolic disease. This review focuses on the ability of fatty acids to influence inflammation and the NLRP3 inflammasome across numerous metabolic tissues in the body. In addition, we explore some perspectives for the future, wherein recent work in the immunology field clearly demonstrates that metabolic reprogramming defines immune cell functionality. Although there is a paucity of information about how diet and fatty acids modulate this process, it is possible that this will open up a new avenue of research relating to nutrient-sensitive metabolic inflammation.
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Affiliation(s)
- Jessica C Ralston
- Nutrigenomics Research Group; UCD Conway Institute of Biomolecular and Biomedical Research; School of Public Health, Physiotherapy, and Sports Science; and Institute of Food and Health; University College Dublin, Dublin 4, Ireland; , , , ,
| | - Claire L Lyons
- Nutrigenomics Research Group; UCD Conway Institute of Biomolecular and Biomedical Research; School of Public Health, Physiotherapy, and Sports Science; and Institute of Food and Health; University College Dublin, Dublin 4, Ireland; , , , ,
| | - Elaine B Kennedy
- Nutrigenomics Research Group; UCD Conway Institute of Biomolecular and Biomedical Research; School of Public Health, Physiotherapy, and Sports Science; and Institute of Food and Health; University College Dublin, Dublin 4, Ireland; , , , ,
| | - Anna M Kirwan
- Nutrigenomics Research Group; UCD Conway Institute of Biomolecular and Biomedical Research; School of Public Health, Physiotherapy, and Sports Science; and Institute of Food and Health; University College Dublin, Dublin 4, Ireland; , , , ,
| | - Helen M Roche
- Nutrigenomics Research Group; UCD Conway Institute of Biomolecular and Biomedical Research; School of Public Health, Physiotherapy, and Sports Science; and Institute of Food and Health; University College Dublin, Dublin 4, Ireland; , , , ,
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48
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Avila-George K, Ramos-Olivares K, Vasquez-Munoz K, Villanueva-Morales V, Reyes-Farias M, Quintero P, Garcia L, Garcia-Diaz DF. Chemically induced hypoxia promotes differential outcomes over preadipocyte- or adipocyte-macrophage communication. Arch Physiol Biochem 2017; 123:175-181. [PMID: 28276712 DOI: 10.1080/13813455.2017.1285318] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Expansion of white adipose tissue induce insufficient vascularization, driving hypoxia and low-grade inflammation. Resident preadipocytes are thought to be involved. We evaluated the effects of hypoxia over preadipocytes and adipocytes, to determine which cellular type impacts the most over macrophages activation. 3T3-L1 cells were either differentiated, or maintained undifferentiated. Each group was subjected to the presence or absence of chemical hypoxia (200 μM CoCl2) for 24 h. Conditioned media were used as treatment for murine RAW264.7 macrophages for 24 h. Gene expression of HIF-1α and TNF-α, and the release of several markers were assessed. It was observed that culture media from hypoxic preadipocytes induced greater expression of inflammatory markers and NO release than culture media from hypoxic adipocytes, by macrophages. Gene expression correlated closer with inflammatory markers release specially on macrophages treated with conditioned media from preadipocytes. Hence, the present work highlights the importance of preadipocytes on inflammatory conditions in vitro.
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Affiliation(s)
- K Avila-George
- a Department of Nutrition , Faculty of Medicine, University of Chile , Santiago , Chile
| | - K Ramos-Olivares
- a Department of Nutrition , Faculty of Medicine, University of Chile , Santiago , Chile
| | - K Vasquez-Munoz
- a Department of Nutrition , Faculty of Medicine, University of Chile , Santiago , Chile
| | - V Villanueva-Morales
- a Department of Nutrition , Faculty of Medicine, University of Chile , Santiago , Chile
| | - M Reyes-Farias
- a Department of Nutrition , Faculty of Medicine, University of Chile , Santiago , Chile
| | - P Quintero
- b Department of Gastroenterology , Faculty of Medicine, Pontifical Catholic University of Chile , Santiago , Chile , and
| | - L Garcia
- c Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, University of Chile , Santiago , Chile
| | - D F Garcia-Diaz
- a Department of Nutrition , Faculty of Medicine, University of Chile , Santiago , Chile
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Weiszenstein M, Shimoda LA, Koc M, Seda O, Polak J. Inhibition of Lipolysis Ameliorates Diabetic Phenotype in a Mouse Model of Obstructive Sleep Apnea. Am J Respir Cell Mol Biol 2017; 55:299-307. [PMID: 26978122 DOI: 10.1165/rcmb.2015-0315oc] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea.
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Affiliation(s)
- Martin Weiszenstein
- 1 Center for Research on Diabetes, Metabolism, and Nutrition, Third Faculty of Medicine.,2 Center of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic
| | - Larissa A Shimoda
- 3 Division of Pulmonary and Critical Care Medicine, Asthma and Allergy Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Michal Koc
- 4 Sports Medicine Department, Third Faculty of Medicine, and
| | - Ondrej Seda
- 5 Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; and
| | - Jan Polak
- 1 Center for Research on Diabetes, Metabolism, and Nutrition, Third Faculty of Medicine.,2 Center of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic.,3 Division of Pulmonary and Critical Care Medicine, Asthma and Allergy Center, Johns Hopkins School of Medicine, Baltimore, Maryland.,6 Second Internal Medicine Department, Vinohrady Teaching Hospital, Prague, Czech Republic
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Sobrinho Santos EM, Guimarães TA, Santos HO, Cangussu LMB, de Jesus SF, Fraga CADC, Cardoso CM, Santos SHS, de Paula AMB, Gomez RS, Guimarães ALS, Farias LC. Leptin acts on neoplastic behavior and expression levels of genes related to hypoxia, angiogenesis, and invasiveness in oral squamous cell carcinoma. Tumour Biol 2017; 39:1010428317699130. [PMID: 28459203 DOI: 10.1177/1010428317699130] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Leptin, one of the main hormones controlling energy homeostasis, has been associated with different cancer types. In oral cancer, its effect is not well understood. We investigated, through in vitro and in vivo assays, whether leptin can affect the neoplastic behavior of oral squamous cell carcinoma. Expression of genes possibly linked to the leptin pathway was assessed in leptin-treated oral squamous cell carcinoma cells and also in tissue samples of oral squamous cell carcinoma and oral mucosa, including leptin, leptin receptor, hypoxia-inducible factor 1-alpha, E-cadherin, matrix metalloproteinase-2, matrix metalloproteinase-9, Col1A1, Ki67, and mir-210. Leptin treatment favored higher rates of cell proliferation and migration, and reduced apoptosis. Accordingly, leptin-treated oral squamous cell carcinoma cells show decreased messenger RNA caspase-3 expression, and increased levels of E-cadherin, Col1A1, matrix metalloproteinase-2, matrix metalloproteinase-9, and mir-210. In tissue samples, hypoxia-inducible factor 1-alpha messenger RNA and protein expression of leptin and leptin receptor were high in oral squamous cell carcinoma cases. Serum leptin levels were increased in first clinical stages of the disease. In animal model, oral squamous cell carcinoma-induced mice show higher leptin receptor expression, and serum leptin level was increased in dysplasia group. Our findings suggest that leptin seems to exert an effect on oral squamous cell carcinoma cells behavior and also on molecular markers related to cell proliferation, migration, and tumor angiogenesis.
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Affiliation(s)
- Eliane Macedo Sobrinho Santos
- 1 Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Brazil.,2 Instituto Federal do Norte de Minas Gerais-Campus Araçuaí, Montes Claros, Brazil
| | | | | | | | | | | | | | - Sérgio Henrique Souza Santos
- 4 Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil
| | | | - Ricardo Santiago Gomez
- 5 Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
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