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Slarve I, Wang Y, Ding Y, Niu X, Tang Q, Jia C, Tu T, Hong H, Zhang G, Gu Y, Xu Z, Skinner S, He L, Hua B, Nguyen P, Zhou Y, Chen L, Ashouri K, Martynova A, Nakhoul C, Rastegarpour A, Alachkar H, Lenz HJ, El-Khoueiry A, Sher L, Chopra S, Yuan L, Stiles BL. Isoform specific regulation of osteopontin by AKT2 in hepatocytes and livers. Cell Signal 2025; 132:111799. [PMID: 40216173 DOI: 10.1016/j.cellsig.2025.111799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Accepted: 04/08/2025] [Indexed: 04/18/2025]
Abstract
Elevated levels of osteopontin (OPN), an inflammatory cytokine, are correlated with chronic inflammatory conditions and liver cancer. In this study, we explored the regulation of OPN in liver and hepatocytes by AKT1 vs. AKT2, the two AKT isoforms expressed in hepatocytes and livers. Using a mouse model lacking PTEN (phosphatase and tensin homologue deleted on chromosome 10), the negative regulator of phosphatidylinositol 3-kinase (PI3K)/AKT signaling, expression of secreted phosphoprotein 1 (Spp1), the gene encoding OPN, was found to be the topmost significantly upregulated gene in the liver. Using an add-back experiment in hepatocytes isolated from these mice, we show that PTEN regulates the expression of Spp1 mRNA as well as OPN protein levels. Exploring how PTEN regulates the expression of Spp1/OPN, we investigated the differential roles of AKT1 vs. AKT2 using hepatocytes isolated from mice lacking each AKT isoform in the liver. We showed here that levels of Spp1/OPN in hepatocytes are lost with deletion of Akt2 but not Akt1. Deletion of Akt2 significantly attenuated both basal expression of OPN and its response to IGF-1 stimulation. AKT1 loss, on the other hand, permitted more robust induction of OPN by IGF-1 stimulation. Furthermore, mice lacking AKT2 and PTEN exhibit significantly lower OPN expression in the liver. Together, this study showed that OPN levels are regulated by the PI3K/AKT signal in hepatocytes and that AKT2 but not AKT1 is responsible for its induction in response to stimulation of the PI3K signaling pathway.
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Affiliation(s)
- Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Yushan Wang
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Yining Ding
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Xiaoteng Niu
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Chengyou Jia
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA; Department of Nuclear Medicine, Central Laboratory for Medical Research, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Taojian Tu
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Guo Zhang
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Yiwei Gu
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Zifei Xu
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Samantha Skinner
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Lina He
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Lulu Chen
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
| | - Karam Ashouri
- Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Anastasia Martynova
- Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Christina Nakhoul
- Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Ali Rastegarpour
- Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Houda Alachkar
- Department of Clinical Pharmacy, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Anthony El-Khoueiry
- Division of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Linda Sher
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Shefali Chopra
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Liyun Yuan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Bangyan Li Stiles
- Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Ham J, Koh J, Kim J, Cho JY, Kim T, Chung DH, Bae YS, Kim HY. Modulating the PD-1-FABP5 axis in ILC2s to regulate adipose tissue metabolism in obesity. Mol Ther 2025; 33:1842-1859. [PMID: 39949060 PMCID: PMC11997476 DOI: 10.1016/j.ymthe.2025.02.015] [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: 08/27/2024] [Revised: 01/09/2025] [Accepted: 02/06/2025] [Indexed: 02/28/2025] Open
Abstract
Obesity is closely linked to metabolic dysregulation and chronic inflammation, which significantly impact immune cell functions in adipose tissue. Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of energy homeostasis, positioning them as promising targets for obesity management. However, the mechanisms governing ILC2 activity and their therapeutic potential in obesity are not fully understood. In this study, we demonstrate that ILC2s in obese adipose tissue exhibit increased PD-1 expression, leading to an exhausted phenotype with diminished cytokine production and proliferation. Elevated osteopontin (OPN) levels in adipose tissue are associated with higher PD-1 expression on ILC2s, while adipocyte-derived PD-L1 interacts with PD-1 to further impair ILC2 functionality. Importantly, blocking PD-1 signaling prevents weight gain and alleviates obesity-related metabolic dysfunctions. In addition, the adoptive transfer of PD-1-deficient ILC2s reduces diabetic phenotypes in obese models. Mechanistically, PD-1 signaling drives metabolic reprogramming in ILC2s, affecting fatty acid uptake and energy metabolism through the downregulation of fatty acid binding protein 5 (FABP5). These results, corroborated by findings in human adipose tissue, suggest a conserved OPN-PD-1 axis. Our study identifies the OPN-PD-1-FABP5 pathway as a crucial regulator of ILC2 function in adipose tissue and presents an emerging immune cell-based therapeutic target for obesity treatment.
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Affiliation(s)
- Jongho Ham
- Laboratory of Mucosal Immunology, Department of Biomedical and Sciences BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, South Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, South Korea; CIRNO, Sungkyunkwan University, Suwon 16419, South Korea
| | - Jaemoon Koh
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, South Korea; Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Jungeun Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, South Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, South Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Kidney Research Institute, Seoul National University Medical Research Center, Seoul 03080, South Korea
| | - TaeSoo Kim
- Department of Life Science, Multitasking Macrophage Research Center, Ewha Womans University, Seoul 03760, South Korea
| | - Doo Hyun Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, South Korea; Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Yong-Soo Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, South Korea; CIRNO, Sungkyunkwan University, Suwon 16419, South Korea
| | - Hye Young Kim
- Laboratory of Mucosal Immunology, Department of Biomedical and Sciences BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, South Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, South Korea; Department of Life Science, Multitasking Macrophage Research Center, Ewha Womans University, Seoul 03760, South Korea; CIRNO, Sungkyunkwan University, Suwon 16419, South Korea.
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Ardizzone A, Siracusa R, Capra AP, Di Paola R, Esposito E, Cuzzocrea S, D'Amico R, Impellizzeri D. Evaluating osteopontin as a biomarker of obesity related complications before and after metabolic and bariatric surgery: A systematic review and meta-analysis. Obes Res Clin Pract 2025; 19:19-27. [PMID: 39884900 DOI: 10.1016/j.orcp.2025.01.010] [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: 10/31/2024] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND/OBJECTIVES Obesity is a major public health concern, significantly elevating the risk of developing comorbid conditions such as type 2 diabetes mellitus and cardio-vascular diseases, while also shortening life expectancy. Currently, metabolic and bariatric surgery (MBS) is one of the most effective long-term interventions for achieving substantial weight loss, alongside notable improvements in overall quality of life. However, evidence suggests that these procedures may negatively affect bone health, leading to an increased risk of fractures. This systematic review and meta-analysis aim to assess the role of Osteopontin (OPN) as a potential biomarker for predicting both persistent inflammation and bone deterioration following MBS. METHODS A comprehensive search of scientific databases including PubMed (MEDLINE), Embase (OVID), and Web of Science, covering literature up to January 31, 2024, identified 6 studies that met the inclusion criteria for the systematic review. For the meta-analysis, data from 5 studies measuring circulating OPN levels pre- and post-surgery were pooled. RESULTS The combined analysis revealed a significant increase in OPN levels after MBS compared to baseline (OR: 24.56; 95 % CI: 13.30-35.81; p < 0.0001). CONCLUSIONS These findings suggest that OPN may serve as a valuable biomarker for monitoring inflammation and assessing the risk of bone-related complications in patients following MBS.
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Affiliation(s)
- Alessio Ardizzone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, Messina 98166, Italy.
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, Messina 98166, Italy.
| | - Anna Paola Capra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, Messina 98166, Italy.
| | - Rosanna Di Paola
- Department of Veterinary Science, University of Messina, Messina 98168, Italy.
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, Messina 98166, Italy.
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, Messina 98166, Italy; Link Campus University, Via del Casale di San Pio V 44, Roma, Italy.
| | - Ramona D'Amico
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, Messina 98166, Italy.
| | - Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, Messina 98166, Italy.
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Vachliotis ID, Anastasilakis AD, Rafailidis V, Polyzos SA. Osteokines in Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2024; 13:703-723. [PMID: 39225951 DOI: 10.1007/s13679-024-00586-9] [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] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
PURPOSE OF REVIEW To critically summarize evidence on the potential role of osteokines in the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS There are emerging data supporting that certain osteokines, which are specific bone-derived proteins, may beneficially or adversely affect hepatic metabolism, and their alterations in the setting of osteoporosis or other bone metabolic diseases may possibly contribute to the development and progression of NAFLD. There is evidence showing a potential bidirectional association between NAFLD and bone metabolism, which may imply the existence of a liver-bone axis. In this regard, osteocalcin, osteoprotegerin, bone morphogenic protein 4 (BMP4) and BMP6 appear to have a positive impact on the liver, thus possibly alleviating NAFLD, whereas osteopontin, receptor activator of nuclear factor kappa Β ligand (RANKL), sclerostin, periostin, BMP8B, and fibroblast growth factor 23 (FGF23) appear to have a negative impact on the liver, thus possibly exacerbating NAFLD. The potential implication of osteokines in NAFLD warrants further animal and clinical research in the field that may possibly result in novel therapeutic targets for NAFLD in the future.
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Affiliation(s)
- Ilias D Vachliotis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | | | - Vasileios Rafailidis
- Department of Clinical Radiology, AHEPA University Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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5
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Zhang J, Sjøberg KA, Gong S, Wang T, Li F, Kuo A, Durot S, Majcher A, Ardicoglu R, Desgeorges T, Mann CG, Soro Arnáiz I, Fitzgerald G, Gilardoni P, Abel ED, Kon S, Olivares-Villagómez D, Zamboni N, Wolfrum C, Hornemann T, Morscher R, Tisch N, Ghesquière B, Kopf M, Richter EA, De Bock K. Endothelial metabolic control of insulin sensitivity through resident macrophages. Cell Metab 2024; 36:2383-2401.e9. [PMID: 39270655 DOI: 10.1016/j.cmet.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/30/2024] [Accepted: 08/15/2024] [Indexed: 09/15/2024]
Abstract
Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.
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Affiliation(s)
- Jing Zhang
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Kim Anker Sjøberg
- August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Songlin Gong
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Tongtong Wang
- Laboratory of Translational Nutritional Biology, Department Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zürich, 8603 Zürich, Switzerland
| | - Fengqi Li
- Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China; Key Laboratory of Immune Response and Immunotherapy, Hefei, China
| | - Andrew Kuo
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Stephan Durot
- Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland
| | - Adam Majcher
- Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute for Clinical Chemistry, University Hospital, Zürich, Switzerland
| | - Raphaela Ardicoglu
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland; Laboratory of Molecular and Behavioral Neuroscience, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland
| | - Thibaut Desgeorges
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Charlotte Greta Mann
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Ines Soro Arnáiz
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Gillian Fitzgerald
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Paola Gilardoni
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - E Dale Abel
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Shigeyuki Kon
- Department of Molecular Immunology, Faculty of Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan
| | - Danyvid Olivares-Villagómez
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nicola Zamboni
- Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland
| | - Christian Wolfrum
- Laboratory of Translational Nutritional Biology, Department Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zürich, 8603 Zürich, Switzerland
| | - Thorsten Hornemann
- Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute for Clinical Chemistry, University Hospital, Zürich, Switzerland
| | - Raphael Morscher
- Pediatric Cancer Metabolism Laboratory, Children`s Research Center, University of Zürich, 8032 Zürich, Switzerland
| | - Nathalie Tisch
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Bart Ghesquière
- Metabolomics Core Facility Leuven, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Manfred Kopf
- Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland
| | - Erik A Richter
- August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Katrien De Bock
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland.
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Ding F, Zheng P, Yan XY, Chen HJ, Fang HT, Luo YY, Peng YX, Zhang L, Yan YE. Adipocyte-secreted PRELP promotes adipocyte differentiation and adipose tissue fibrosis by binding with p75 NTR to activate FAK/MAPK signaling. Int J Biol Macromol 2024; 279:135376. [PMID: 39244119 DOI: 10.1016/j.ijbiomac.2024.135376] [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: 05/03/2024] [Revised: 08/20/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024]
Abstract
Adipocyte-secreted factors intricately regulate adipose tissue function, and the underlying molecular mechanisms are only partially understood. However, the function of PRELP, which is a key component of the extracellular matrix (ECM) in adipocytes, remains largely unknown. In this study, we demonstrate that PRELP was upregulated in both obese humans and mice, which exhibited a positive correlation with metabolic disorders. PRELP knockout could resist HFD-induced obesity and inhibit adipocyte differentiation. PRELP knockout improved glucose tolerance, insulin sensitivity and alleviated adipose tissue fibrosis. Mechanistically, PRELP was secreted into the ECM and bound to the extracellular domain of its receptor p75NTR in adipocytes, which further activated the FAK/MAPK (JNK, p38 MAPK, ERK1/2) signaling pathway, promoting adipocyte differentiation and exacerbating adipocyte fibrosis. Adipocyte PRELP plays a pivotal role in regulating obesity and adipose tissue fibrosis through an autocrine manner, and PRELP may be a therapeutic target for obesity and its related metabolic disorders.
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Affiliation(s)
- Fei Ding
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Peng Zheng
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Xi-Yue Yan
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Hui-Jian Chen
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Hong-Ting Fang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Yuan-Yuan Luo
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Yu-Xuan Peng
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Li Zhang
- Demonstration Center for Experimental Basic Medicine Education, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - You-E Yan
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
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7
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Panda VK, Mishra B, Nath AN, Butti R, Yadav AS, Malhotra D, Khanra S, Mahapatra S, Mishra P, Swain B, Majhi S, Kumari K, Radharani NNV, Kundu GC. Osteopontin: A Key Multifaceted Regulator in Tumor Progression and Immunomodulation. Biomedicines 2024; 12:1527. [PMID: 39062100 PMCID: PMC11274826 DOI: 10.3390/biomedicines12071527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
The tumor microenvironment (TME) is composed of various cellular components such as tumor cells, stromal cells including fibroblasts, adipocytes, mast cells, lymphatic vascular cells and infiltrating immune cells, macrophages, dendritic cells and lymphocytes. The intricate interplay between these cells influences tumor growth, metastasis and therapy failure. Significant advancements in breast cancer therapy have resulted in a substantial decrease in mortality. However, existing cancer treatments frequently result in toxicity and nonspecific side effects. Therefore, improving targeted drug delivery and increasing the efficacy of drugs is crucial for enhancing treatment outcome and reducing the burden of toxicity. In this review, we have provided an overview of how tumor and stroma-derived osteopontin (OPN) plays a key role in regulating the oncogenic potential of various cancers including breast. Next, we dissected the signaling network by which OPN regulates tumor progression through interaction with selective integrins and CD44 receptors. This review addresses the latest advancements in the roles of splice variants of OPN in cancer progression and OPN-mediated tumor-stromal interaction, EMT, CSC enhancement, immunomodulation, metastasis, chemoresistance and metabolic reprogramming, and further suggests that OPN might be a potential therapeutic target and prognostic biomarker for the evolving landscape of cancer management.
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Affiliation(s)
- Venketesh K. Panda
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Barnalee Mishra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Angitha N. Nath
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Ramesh Butti
- Division of Hematology and Oncology, Department of Internal Medicine, Southwestern Medical Center, University of Texas, Dallas, TX 75235, USA;
| | - Amit Singh Yadav
- Biomedical Centre, Faculty of Medicine, Lund University, 223 62 Lund, Sweden; (A.S.Y.); (N.N.V.R.)
| | - Diksha Malhotra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Sinjan Khanra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Samikshya Mahapatra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Priyanka Mishra
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Biswajit Swain
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Sambhunath Majhi
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - Kavita Kumari
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
| | - N. N. V. Radharani
- Biomedical Centre, Faculty of Medicine, Lund University, 223 62 Lund, Sweden; (A.S.Y.); (N.N.V.R.)
| | - Gopal C. Kundu
- School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India; (V.K.P.); (B.M.); (A.N.N.); (D.M.); (S.K.); (S.M.); (P.M.); (B.S.); (S.M.); (K.K.)
- Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed to be University, Bhubaneswar 751024, India
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8
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Huang T, Lu Z, Wang Z, Cheng L, Gao L, Gao J, Zhang N, Geng CA, Zhao X, Wang H, Wong CW, Yeung KWK, Pan H, Lu WW, Guan M. Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow. Nat Commun 2024; 15:3769. [PMID: 38704393 PMCID: PMC11069533 DOI: 10.1038/s41467-024-48255-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 04/23/2024] [Indexed: 05/06/2024] Open
Abstract
Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.
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Affiliation(s)
- Tongling Huang
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Zhaocheng Lu
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Zihui Wang
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lixin Cheng
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital, Shenzhen, China
| | - Lu Gao
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jun Gao
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Ning Zhang
- Neuroscience Center, Shantou University Medical College, Shantou, China
| | - Chang-An Geng
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
| | - Xiaoli Zhao
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Huaiyu Wang
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | | | - Kelvin W K Yeung
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Haobo Pan
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - William Weijia Lu
- Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Min Guan
- Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
- University of Chinese Academy of Sciences, Beijing, China.
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9
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Fukusada S, Shimura T, Natsume M, Nishigaki R, Okuda Y, Iwasaki H, Sugimura N, Kitagawa M, Katano T, Tanaka M, Ozeki K, Kubota E, Hayashi K, Kataoka H. Osteopontin secreted from obese adipocytes enhances angiogenesis and promotes progression of pancreatic ductal adenocarcinoma in obesity. Cell Oncol (Dordr) 2024; 47:229-244. [PMID: 37640984 DOI: 10.1007/s13402-023-00865-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2023] [Indexed: 08/31/2023] Open
Abstract
PURPOSE Obesity is a risk factor and poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms remain unclear. METHODS PDAC cells and obese visceral adipocytes (O-Ad) derived from mice and humans were used to analyze interactions between the two cell types, and human microvascular endothelial cells were used for angiogenesis assay. A xenograft mouse model with subcutaneously injected PDAC cells was used for animal studies. The relationship between visceral fat and prognosis was analyzed using resected tissues from PDAC patients with and without obesity. RESULTS Conditioned media (CM) from O-Ad significantly increased PDAC cell growth and migration and angiogenic capacity in both human and mice cells, and blocking osteopontin (OPN) in O-Ad canceled O-Ad-induced effects in both mouse and human cells. In addition, O-Ad directly increased the migratory and tube-forming capacities of endothelial cells, while blocking OPN canceled these effects. O-Ad increased AKT phosphorylation and VEGFA expression in both PDAC and endothelial cells, and OPN inhibition in O-Ad canceled those O-Ad-induced effects. In the xenograft model, PDAC tumor volume was significantly increased in obese mice compared with lean mice, whereas blocking OPN significantly inhibited obesity-accelerated tumor growth. OPN expression in adipose tissues adjacent to human PDAC tumor was significantly higher in obese patients than in non-obese patients. In PDAC patients with obesity, high OPN expression in adipose tissues was significantly associated with poor prognosis. CONCLUSION Obese adipocytes trigger aggressive transformation in PDAC cells to induce PDAC progression and accelerate angiogenesis via OPN secretion.
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Affiliation(s)
- Shigeki Fukusada
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Makoto Natsume
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Ruriko Nishigaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Yusuke Okuda
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hiroyasu Iwasaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Naomi Sugimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Mika Kitagawa
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takahito Katano
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Mamoru Tanaka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Keiji Ozeki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Eiji Kubota
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Kazuki Hayashi
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
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10
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Engin A. Lipid Storage, Lipolysis, and Lipotoxicity in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:97-129. [PMID: 39287850 DOI: 10.1007/978-3-031-63657-8_4] [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
The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride (triacylglycerol: TAG) turnover. Hypoxia in obese adipose tissue due to hypertrophic adipocytes results in excess deposition of extracellular matrix (ECM) components. Cluster of differentiation (CD) 44, as the main receptor of the extracellular matrix component regulates cell-cell and cell-matrix interactions including diet-induced insulin resistance. Excess TAGs, sterols, and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets (LDs). Once LDs are formed, they grow up because of the excessive amount of intracellular FFA stored and reach a final size. The ratio of FFA turnover/lipolysis decreases significantly with increases in the degree of obesity. Dysfunctional adipose tissue is unable to expand further to store excess dietary lipids, increased fluxes of plasma FFAs lead to ectopic fatty acid deposition and lipotoxicity. Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. Adipocyte death is a prerequisite for the transition from hypertrophic to hyperplastic obesity. Increased adipocyte number in obesity has life-long effects on white adipose tissue mass. The positive correlation between the adipose tissue volume and magnetic resonance imaging proton density fat fraction estimation is used for characterization of the obesity phenotype, as well as the risk stratification and selection of appropriate treatment strategies. In obese patients with type 2 diabetes, visceral adipocytes exposed to chronic/intermittent hyperglycemia develop a new microRNAs' (miRNAs') expression pattern. Visceral preadipocytes memorize the effect of hyperglycemia via changes in miRNAs' expression profile and contribute to the progression of diabetic phenotype. Nonsteroidal anti-inflammatory drugs, metformin, and statins can be beneficial in treating the local or systemic consequences of white adipose tissue inflammation. Rapamycin inhibits leptin-induced LD formation. Collectively, in this chapter, the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of LD interactions with the other cellular organelles are reviewed. Furthermore, clinical perspective of fat cell turnover in obesity is also debated.
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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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11
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Al Zein M, Zein O, Diab R, Dimachkie L, Sahebkar A, Al-Asmakh M, Kobeissy F, Eid AH. Intermittent fasting favorably modulates adipokines and potentially attenuates atherosclerosis. Biochem Pharmacol 2023; 218:115876. [PMID: 37871879 DOI: 10.1016/j.bcp.2023.115876] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 10/25/2023]
Abstract
Adipose tissue is now recognized as an endocrine organ that secretes bioactive molecules called adipokines. These biomolecules regulate key physiological functions, including insulin sensitivity, energy metabolism, appetite regulation, endothelial function and immunity. Dysregulated secretion of adipokines is intimately associated with obesity, and translates into increased risk of obesity-related cardiovasculo-metabolic diseases. In particular, emerging evidence suggests that adipokine imbalance contributes to the pathogenesis of atherosclerosis. One of the promising diet regimens that is beneficial in the fight against obesity and cardiometabolic disorders is intermittent fasting (IF). Indeed, IF robustly suppresses inflammation, meditates weight loss and mitigates many aspects of the cardiometabolic syndrome. In this paper, we review the main adipokines and their role in atherosclerosis, which remains a major contributor to cardiovascular-associated morbidity and mortality. We further discuss how IF can be employed as an effective management modality for obesity-associated atherosclerosis. By exploring a plethora of the beneficial effects of IF, particularly on inflammatory markers, we present IF as a possible intervention to help prevent atherosclerosis.
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Affiliation(s)
- Mohammad Al Zein
- Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Omar Zein
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rawan Diab
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Lina Dimachkie
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maha Al-Asmakh
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar; Biomedical Research Center, Qatar University, Doha, Qatar
| | - Firas Kobeissy
- Department of Neurobiology and Neuroscience, Morehouse School of Medicine, Atlanta, GA, USA
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar.
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12
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Lischka J, Schanzer A, de Gier C, Greber-Platzer S, Zeyda M. Macrophage-associated markers of metaflammation are linked to metabolic dysfunction in pediatric obesity. Cytokine 2023; 171:156372. [PMID: 37729736 DOI: 10.1016/j.cyto.2023.156372] [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: 08/11/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 09/22/2023]
Abstract
BACKGPOUND Metabolically driven chronic low-grade adipose tissue inflammation, so-called metaflammation, is a central feature in obesity. This inflammatory tone is largely driven by adipose tissue macrophages (ATM), which express pro- and anti-inflammatory markers and cytokines such as, e.g., IL-1 receptor antagonist (IL-1RA), CD163 and osteopontin (OPN). Metaflammation ultimately leads to the development of cardiometabolic diseases. This study aimed to evaluate the association between selected adipose tissue macrophage-associated markers and metabolic comorbidities in pediatric obesity. METHODS From a pediatric cohort with obesity (n = 108), clinically thoroughly characterized including diverse routine blood parameters, oral glucose tolerance test and liver MRI, plasma IL-1RA, soluble (s)CD163 and OPN were measured by ELISA. RESULTS We observed significantly higher IL-1RA, sCD163, and OPN levels in the plasma of children with metabolic-dysfunction associated fatty liver disease (MAFLD) and metabolic syndrome. Moreover, IL-1RA and sCD163 correlated with hepatic disease and apoptosis markers alanine aminotransferase and CK-18. IL-1RA concentrations additionally correlated with insulin resistance, while children with disturbed glucose metabolism had significantly higher levels of sCD163. CONCLUSION MAFLD and other metabolic disorders in pediatric patients with obesity are associated with an elevation of adipose tissue macrophage-related inflammation markers.
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Affiliation(s)
- Julia Lischka
- Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria; Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria
| | - Andrea Schanzer
- Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Charlotte de Gier
- Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Susanne Greber-Platzer
- Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Maximilian Zeyda
- Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
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13
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Soysouvanh F, Rousseau D, Bonnafous S, Bourinet M, Strazzulla A, Patouraux S, Machowiak J, Farrugia MA, Iannelli A, Tran A, Anty R, Luci C, Gual P. Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD. Obesity (Silver Spring) 2023; 31:2568-2582. [PMID: 37724058 DOI: 10.1002/oby.23868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 06/20/2023] [Accepted: 06/26/2023] [Indexed: 09/20/2023]
Abstract
OBJECTIVE This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T-cell regulation in initiation of obesity-driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic-associated fatty liver disease (MAFLD) development. METHODS SPP1 and T-cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individuals with obesity. The role of SPP1 on T cells was evaluated in Spp1-knockout mice challenged with a high-fat diet. RESULTS In humans with obesity, elevated SPP1 expression in AT was parallel to T-cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T-cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T-cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1) polarization of AT CD4+ and CD8+ T cells. In addition, Spp1 deficiency significantly reduced obesity-associated liver steatosis and inflammation. CONCLUSIONS Current findings highlight a critical role of SPP1 in the initiation of obesity-driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment.
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Affiliation(s)
| | | | | | - Manon Bourinet
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
| | | | | | - Jean Machowiak
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
| | | | | | - Albert Tran
- Université Côte d'Azur, CHU, INSERM, U1065, C3M, Nice, France
| | - Rodolphe Anty
- Université Côte d'Azur, CHU, INSERM, U1065, C3M, Nice, France
| | - Carmelo Luci
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
| | - Philippe Gual
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
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14
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Pestel J, Blangero F, Watson J, Pirola L, Eljaafari A. Adipokines in obesity and metabolic-related-diseases. Biochimie 2023; 212:48-59. [PMID: 37068579 DOI: 10.1016/j.biochi.2023.04.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/03/2023] [Accepted: 04/13/2023] [Indexed: 04/19/2023]
Abstract
The discovery of leptin in the 1990s led to a reconsideration of adipose tissue (AT) as not only a fatty acid storage organ, but also a proper endocrine tissue. AT is indeed capable of secreting bioactive molecules called adipokines for white AT or batokines for brown/beige AT, which allow communication with numerous organs, especially brain, heart, liver, pancreas, and/or the vascular system. Adipokines exert pro or anti-inflammatory activities. An equilibrated balance between these two sets ensures homeostasis of numerous tissues and organs. During the development of obesity, AT remodelling leads to an alteration of its endocrine activity, with increased secretion of pro-inflammatory adipokines relative to the anti-inflammatory ones, as shown in the graphical abstract. Pro-inflammatory adipokines take part in the initiation of local and systemic inflammation during obesity and contribute to comorbidities associated to obesity, as detailed in the present review.
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Affiliation(s)
- Julien Pestel
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Ferdinand Blangero
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Julia Watson
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Luciano Pirola
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Assia Eljaafari
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France; Hospices Civils de Lyon: 2 quai des Célestins, 69001 Lyon, France.
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15
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Kuziel G, Moore BN, Arendt LM. Obesity and Fibrosis: Setting the Stage for Breast Cancer. Cancers (Basel) 2023; 15:cancers15112929. [PMID: 37296891 DOI: 10.3390/cancers15112929] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Obesity is a rising health concern and is linked to a worsened breast cancer prognosis. Tumor desmoplasia, which is characterized by elevated numbers of cancer-associated fibroblasts and the deposition of fibrillar collagens within the stroma, may contribute to the aggressive clinical behavior of breast cancer in obesity. A major component of the breast is adipose tissue, and fibrotic changes in adipose tissue due to obesity may contribute to breast cancer development and the biology of the resulting tumors. Adipose tissue fibrosis is a consequence of obesity that has multiple sources. Adipocytes and adipose-derived stromal cells secrete extracellular matrix composed of collagen family members and matricellular proteins that are altered by obesity. Adipose tissue also becomes a site of chronic, macrophage-driven inflammation. Macrophages exist as a diverse population within obese adipose tissue and mediate the development of fibrosis through the secretion of growth factors and matricellular proteins and interactions with other stromal cells. While weight loss is recommended to resolve obesity, the long-term effects of weight loss on adipose tissue fibrosis and inflammation within breast tissue are less clear. Increased fibrosis within breast tissue may increase the risk for tumor development as well as promote characteristics associated with tumor aggressiveness.
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Affiliation(s)
- Genevra Kuziel
- Cancer Biology Graduate Program, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA
| | - Brittney N Moore
- Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA
| | - Lisa M Arendt
- Cancer Biology Graduate Program, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA
- Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA
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16
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Csader S, Ismaiah MJ, Kuningas T, Heinäniemi M, Suhonen J, Männistö V, Pentikäinen H, Savonen K, Tauriainen MM, Galano JM, Lee JCY, Rintamäki R, Karisola P, El-Nezami H, Schwab U. Twelve Weeks of High-Intensity Interval Training Alters Adipose Tissue Gene Expression but Not Oxylipin Levels in People with Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:ijms24108509. [PMID: 37239856 DOI: 10.3390/ijms24108509] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/04/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Lifestyle modifications, including increased physical activity and exercise, are recommended for non-alcoholic fatty liver disease (NAFLD). Inflamed adipose tissue (AT) contributes to the progression and development of NAFLD and oxylipins such as hydroxyeicosatetraenoic acids (HETE), hydroxydocosahexanenoic acids (HDHA), prostaglandins (PEG2), and isoprostanoids (IsoP), which all may play a role in AT homeostasis and inflammation. To investigate the role of exercise without weight loss on AT and plasma oxylipin concentrations in NAFLD subjects, we conducted a 12-week randomized controlled exercise intervention. Plasma samples from 39 subjects and abdominal subcutaneous AT biopsy samples from 19 subjects were collected both at the beginning and the end of the exercise intervention. In the AT of women, a significant reduction of gene expression of hemoglobin subunits (HBB, HBA1, HBA2) was observed within the intervention group during the 12-week intervention. Their expression levels were negatively associated with VO2max and maxW. In addition, pathways involved in adipocyte morphology alterations significantly increased, whereas pathways in fat metabolism, branched-chain amino acids degradation, and oxidative phosphorylation were suppressed in the intervention group (p < 0.05). Compared to the control group, in the intervention group, the ribosome pathway was activated, but lysosome, oxidative phosphorylation, and pathways of AT modification were suppressed (p < 0.05). Most of the oxylipins (HETE, HDHA, PEG2, and IsoP) in plasma did not change during the intervention compared to the control group. 15-F2t-IsoP significantly increased in the intervention group compared to the control group (p = 0.014). However, this oxylipin could not be detected in all samples. Exercise intervention without weight loss may influence the AT morphology and fat metabolism at the gene expression level in female NAFLD subjects.
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Affiliation(s)
- Susanne Csader
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70200 Kuopio, Finland
| | - Marsena Jasiel Ismaiah
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, China
| | - Tiina Kuningas
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland
| | - Merja Heinäniemi
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland
| | - Janne Suhonen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, FI-70210 Kuopio, Finland
| | - Heikki Pentikäinen
- Kuopio Research Institute of Exercise Medicine, FI-70210 Kuopio, Finland
| | - Kai Savonen
- Kuopio Research Institute of Exercise Medicine, FI-70210 Kuopio, Finland
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, FI-70210 Kuopio, Finland
| | - Milla-Maria Tauriainen
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70200 Kuopio, Finland
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, FI-70210 Kuopio, Finland
| | - Jean-Marie Galano
- Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM, F-34093 Montpellier, France
| | - Jetty Chung-Yung Lee
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, China
| | - Reeta Rintamäki
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, FI-70210 Kuopio, Finland
| | - Piia Karisola
- Faculty of Medicine, Human Microbiome Research Program, University of Helsinki, FI-00100 Helsinki, Finland
| | - Hani El-Nezami
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70200 Kuopio, Finland
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, China
| | - Ursula Schwab
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70200 Kuopio, Finland
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, FI-70210 Kuopio, Finland
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17
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Negri AL, Spivacow FR. Kidney stone matrix proteins: Role in stone formation. World J Nephrol 2023; 12:21-28. [PMID: 37035509 PMCID: PMC10075018 DOI: 10.5527/wjn.v12.i2.21] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/18/2023] [Accepted: 03/17/2023] [Indexed: 03/21/2023] Open
Abstract
Stone formation is induced by an increased level of urine crystallization promoters and reduced levels of its inhibitors. Crystallization inhibitors include citrate, magnesium, zinc, and organic compounds such as glycosaminoglycans. In the urine, there are various proteins, such as uromodulin (Tamm-Horsfall protein), calgranulin, osteopontin, bikunin, and nephrocalcin, that are present in the stone matrix. The presence of several carboxyl groups in these macromolecules reduces calcium oxalate monohydrate crystal adhesion to the urinary epithelium and could potentially protect against lithiasis. Proteins are the most abundant component of kidney stone matrix, and their presence may reflect the process of stone formation. Many recent studies have explored the proteomics of urinary stones. Among the stone matrix proteins, the most frequently identified were uromodulin, S100 proteins (calgranulins A and B), osteopontin, and several other proteins typically engaged in inflammation and immune response. The normal level and structure of these macromolecules may constitute protection against calcium salt formation. Paradoxically, most of them may act as both promoters and inhibitors depending on circumstances. Many of these proteins have other functions in modulating oxidative stress, immune function, and inflammation that could also influence stone formation. Yet, the role of these kidney stone matrix proteins needs to be established through more studies comparing urinary stone proteomics between stone formers and non-stone formers.
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Affiliation(s)
- Armando Luis Negri
- Department of Physiology and Biophysics, Universidad del Salvador, Instituto de Investigaciones Metabólicas, Buenos Aires 1012, Argentina
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18
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Levy E, Marcil V, Tagharist Ép Baumel S, Dahan N, Delvin E, Spahis S. Lactoferrin, Osteopontin and Lactoferrin–Osteopontin Complex: A Critical Look on Their Role in Perinatal Period and Cardiometabolic Disorders. Nutrients 2023; 15:nu15061394. [PMID: 36986124 PMCID: PMC10052990 DOI: 10.3390/nu15061394] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023] Open
Abstract
Milk-derived bioactive proteins have increasingly gained attention and consideration throughout the world due to their high-quality amino acids and multiple health-promoting attributes. Apparently, being at the forefront of functional foods, these bioactive proteins are also suggested as potential alternatives for the management of various complex diseases. In this review, we will focus on lactoferrin (LF) and osteopontin (OPN), two multifunctional dairy proteins, as well as to their naturally occurring bioactive LF–OPN complex. While describing their wide variety of physiological, biochemical, and nutritional functionalities, we will emphasize their specific roles in the perinatal period. Afterwards, we will evaluate their ability to control oxidative stress, inflammation, gut mucosal barrier, and intestinal microbiota in link with cardiometabolic disorders (CMD) (obesity, insulin resistance, dyslipidemia, and hypertension) and associated complications (diabetes and atherosclerosis). This review will not only attempt to highlight the mechanisms of action, but it will critically discuss the potential therapeutic applications of the underlined bioactive proteins in CMD.
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Affiliation(s)
- Emile Levy
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Valérie Marcil
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Sarah Tagharist Ép Baumel
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Noam Dahan
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
| | - Edgard Delvin
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Biochemistry &Molecular Medicine, Faculty of Medicine, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Schohraya Spahis
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Biochemistry &Molecular Medicine, Faculty of Medicine, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
- Correspondence: ; Tel.: +1-(514)-345-4832
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19
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Lai F, Wang J, Tang H, Huang P, Liu J, He G, Zhou M, Tao X, Tang K. VEGF promotes tendon regeneration of aged rats by inhibiting adipogenic differentiation of tendon stem/progenitor cells and promoting vascularization. FASEB J 2022; 36:e22433. [PMID: 35867348 DOI: 10.1096/fj.202200213r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/23/2022] [Accepted: 06/13/2022] [Indexed: 11/11/2022]
Abstract
Studies have shown that the stem cell microenvironment is a key factor for stem cell maintenance or differentiation. In this study, we compared the expression of 23 cytokines such as IL-6, IL-10, and TNFα between young and aged rats during patellar tendon repair by cytokine microarray, and found that significant difference between IL-10, G-CSF, and VEGF at 3, 7, or 14 days post-operatively. The effects of these factors on adipogenic differentiation of TPSCs were examined through western blot and oil red O experiments. It was shown that VEGF had an inhibitive effect on the adipogenic differentiation of TPSCs. SPP-1 was figured out as our target by RNA sequencing and confirmed by western blot in vitro. Further in vivo studies showed that adipocyte accumulation was also decreased in the tendons of aged rats after injection of VEGF and the histological score and biomechanical property were also improved via targeting SPP-1. Furthermore, histochemical results showed that vascularization of the injury sites was significantly elevated. In conclusion, VEGF not only plays an important role in decreasing adipocyte accumulation but also improves vascularization of the tendon during aged tendon healing. We believe active regulation of VEGF may improve the treatment of age-related tendon diseases and tendon injuries.
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Affiliation(s)
- Fan Lai
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jingjing Wang
- Department of Blood Transfusion, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hong Tang
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Pan Huang
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Juan Liu
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Gang He
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Mei Zhou
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Xu Tao
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
| | - Kanglai Tang
- Department of Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, China
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20
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Xiao L, Xu Q, Liu X, Chan S, Luo Y, He S, Fang M. The Novel-miR-659/SPP1 Interaction Regulates Fat Deposition in Castrated Male Pigs. Animals (Basel) 2022; 12:ani12080944. [PMID: 35454191 PMCID: PMC9031235 DOI: 10.3390/ani12080944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/20/2022] [Accepted: 03/31/2022] [Indexed: 11/26/2022] Open
Abstract
Simple Summary Castration is a standard method for eliminating boar taint in industrial hog production, but it also causes enormous fat accumulation in the carcass. Secreted phosphoprotein 1 (SPP1) was selected to investigate its functions on the regulation of adipose deposition based on our previous data. In the present study, SPP1 overexpression and interference bidirectionally verified that SPP1 inhibited adipogenic differentiation of porcine bone marrow mesenchymal stem cells (pBMSCs). Testosterone-treated cell models were used to simulate the androgen status of intact pigs, and testosterone addition influenced SPP1 mRNA levels during the differentiation of pBMSCs. Moreover, we identified novel-miR-659 and targeted the 3′ untranslated region of SPP1 based on bioinformatics analysis and dual-luciferase assays, and found that the novel-miR-659 upregulation promoted adipogenesis while novel-miR-659 downregulation suppressed adipogenesis in pBMSCs detected by Oil Red O staining and adipogenic markers. Collectively, the interaction between novel-miR-659 and SPP1 can regulate adipose accumulation in castrated male pigs. Our data provide a theoretical basis for further study on the fat deposition mechanism caused by castration. Abstract Castration is usually used to remove boar taint in commercial pork production, but the adipose accumulation was increased excessively, which affected the meat quality of pigs. Based on our previous study, secreted phosphoprotein 1 (SPP1) was significantly differentially expressed between castrated and intact male pigs. However, the role of SPP1 in regulating adipose growth and fat storage caused by castration is unknown. In this study, SPP1 was identified to inhibit adipogenesis by the expression of adipogenic markers PPARγ and FABP4 as well as Oil red staining assay during differentiation of porcine bone marrow mesenchymal stem cells (pBMSCs). Subsequently, testosterone was used to treat pBMSCs to simulate the androgen status of intact pigs. Compared with the control groups without testosterone, the SPP1 expression in the testosterone group was markedly increased in the late stage of pBMSCs differentiation. Furthermore, novel-miR-659 was predicted by TargetScan and miRDB to target SPP1 and verified through a dual-luciferase reporter assay. Oil Red O staining assay indicated that novel-miR-659 overexpression significantly promoted adipogenesis, whereas novel-miR-659 inhibition suppressed adipogenesis. The expressions of adipogenic markers PPARγ and FABP4 showed the same tendency. Taken together, our study found that the targeted interaction between novel-miR-659 and SPP1 is involved in regulation of fat deposition in castrated male pigs.
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Affiliation(s)
- Lianmei Xiao
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (L.X.); (Q.X.); (X.L.); (S.C.); (Y.L.); (S.H.)
| | - Qiao Xu
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (L.X.); (Q.X.); (X.L.); (S.C.); (Y.L.); (S.H.)
- School of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ximing Liu
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (L.X.); (Q.X.); (X.L.); (S.C.); (Y.L.); (S.H.)
| | - Shuheng Chan
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (L.X.); (Q.X.); (X.L.); (S.C.); (Y.L.); (S.H.)
| | - Yabiao Luo
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (L.X.); (Q.X.); (X.L.); (S.C.); (Y.L.); (S.H.)
| | - Shuaihan He
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (L.X.); (Q.X.); (X.L.); (S.C.); (Y.L.); (S.H.)
| | - Meiying Fang
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (L.X.); (Q.X.); (X.L.); (S.C.); (Y.L.); (S.H.)
- Sanya Institute of China Agricultural University, Sanya 572025, China
- Correspondence: ; Tel./Fax: +86-10-62734943
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21
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Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue. Cancers (Basel) 2022; 14:cancers14071679. [PMID: 35406450 PMCID: PMC8996963 DOI: 10.3390/cancers14071679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work. Abstract The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.
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22
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Imbert A, Vialaneix N, Marquis J, Vion J, Charpagne A, Metairon S, Laurens C, Moro C, Boulet N, Walter O, Lefebvre G, Hager J, Langin D, Saris WHM, Astrup A, Viguerie N, Valsesia A. Network Analyses Reveal Negative Link Between Changes in Adipose Tissue GDF15 and BMI During Dietary-induced Weight Loss. J Clin Endocrinol Metab 2022; 107:e130-e142. [PMID: 34415992 DOI: 10.1210/clinem/dgab621] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Adipose tissue (AT) transcriptome studies provide holistic pictures of adaptation to weight and related bioclinical settings changes. OBJECTIVE To implement AT gene expression profiling and investigate the link between changes in bioclinical parameters and AT gene expression during 3 steps of a 2-phase dietary intervention (DI). METHODS AT transcriptome profiling was obtained from sequencing 1051 samples, corresponding to 556 distinct individuals enrolled in a weight loss intervention (8-week low-calorie diet (LCD) at 800 kcal/day) followed with a 6-month ad libitum randomized DI. Transcriptome profiles obtained with QuantSeq sequencing were benchmarked against Illumina RNAseq. Reverse transcription quantitative polymerase chain reaction was used to further confirm associations. Cell specificity was assessed using freshly isolated cells and THP-1 cell line. RESULTS During LCD, 5 modules were found, of which 3 included at least 1 bioclinical variable. Change in body mass index (BMI) connected with changes in mRNA level of genes with inflammatory response signature. In this module, change in BMI was negatively associated with changes in expression of genes encoding secreted protein (GDF15, CCL3, and SPP1). Through all phases of the DI, change in GDF15 was connected to changes in SPP1, CCL3, LIPA and CD68. Further characterization showed that these genes were specific to macrophages (with LIPA, CD68 and GDF15 expressed in anti-inflammatory macrophages) and GDF15 also expressed in preadipocytes. CONCLUSION Network analyses identified a novel AT feature with GDF15 upregulated with calorie restriction induced weight loss, concomitantly to macrophage markers. In AT, GDF15 was expressed in preadipocytes and macrophages where it was a hallmark of anti-inflammatory cells.
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Affiliation(s)
- Alyssa Imbert
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Metabolic Disorders and Diabesity, 31400, Toulouse, France
- Université de Toulouse, UMR1297, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, 31400, Toulouse, France
- INRAE, UR875 Mathématiques et Informatique Appliquées Toulouse, F-31326 Castanet-Tolosan, France
| | - Nathalie Vialaneix
- INRAE, UR875 Mathématiques et Informatique Appliquées Toulouse, F-31326 Castanet-Tolosan, France
| | - Julien Marquis
- Université de Lausanne, Genomic Technologies Facility, 1015, Lausanne, Switzerland
| | - Julie Vion
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Metabolic Disorders and Diabesity, 31400, Toulouse, France
- Université de Toulouse, UMR1297, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, 31400, Toulouse, France
| | - Aline Charpagne
- Nestlé Institute of Health Sciences, Metabolic Health Department, 1015, Lausanne, Switzerland
| | - Sylviane Metairon
- Nestlé Institute of Health Sciences, Metabolic Health Department, 1015, Lausanne, Switzerland
| | - Claire Laurens
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Metabolic Disorders and Diabesity, 31400, Toulouse, France
- Université de Toulouse, UMR1297, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, 31400, Toulouse, France
| | - Cedric Moro
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Metabolic Disorders and Diabesity, 31400, Toulouse, France
- Université de Toulouse, UMR1297, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, 31400, Toulouse, France
| | - Nathalie Boulet
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Metabolic Disorders and Diabesity, 31400, Toulouse, France
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Adipose tissue, microbiota and cardiometabolic flexibility, 31400, Toulouse, France
| | - Ondine Walter
- Nestlé Institute of Health Sciences, Metabolic Health Department, 1015, Lausanne, Switzerland
| | - Grégory Lefebvre
- Nestlé Institute of Health Sciences, Metabolic Health Department, 1015, Lausanne, Switzerland
| | - Jörg Hager
- Nestlé Institute of Health Sciences, Metabolic Health Department, 1015, Lausanne, Switzerland
| | - Dominique Langin
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Metabolic Disorders and Diabesity, 31400, Toulouse, France
- Université de Toulouse, UMR1297, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, 31400, Toulouse, France
- Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France
- Toulouse University Hospitals, Laboratory of Clinical Biochemistry, 31000, Toulouse, France
| | - Wim H M Saris
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Arne Astrup
- Department of Nutrition, Exercise and Sports, Faculty of Sciences, University of Copenhagen, Denmark
| | - Nathalie Viguerie
- Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Institute of Metabolic and Cardiovascular Diseases, Team Metabolic Disorders and Diabesity, 31400, Toulouse, France
- Université de Toulouse, UMR1297, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, 31400, Toulouse, France
- Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France
| | - Armand Valsesia
- Nestlé Institute of Health Sciences, Metabolic Health Department, 1015, Lausanne, Switzerland
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23
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Bai RJ, Li YS, Zhang FJ. Osteopontin, a bridge links osteoarthritis and osteoporosis. Front Endocrinol (Lausanne) 2022; 13:1012508. [PMID: 36387862 PMCID: PMC9649917 DOI: 10.3389/fendo.2022.1012508] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/13/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoarthritis (OA) is the most prevalent joint disease characterized by degradation of articular cartilage, inflammation, and changes in periarticular and subchondral bone of joints. Osteoporosis (OP) is another systemic skeletal disease characterized by low bone mass and bone mineral density (BMD) accompanied by microarchitectural deterioration in bone tissue and increased bone fragility and fracture risk. Both OA and OP are mainly affected on the elderly people. Recent studies have shown that osteopontin (OPN) plays a vital role in bone metabolism and homeostasis. OPN involves these biological activities through participating in the proliferation, migration, differentiation, and adhesion of several bone-related cells, including chondrocytes, synoviocytes, osteoclasts, osteoblasts, and marrow mesenchymal stem cells (MSCs). OPN has been demonstrated to be closely related to the occurrence and development of many bone-related diseases, such as OA and OP. This review summarizes the role of OPN in regulating inflammation activity and bone metabolism in OA and OP. Furthermore, some drugs that targeted OPN to treat OA and OP are also summarized in the review. However, the complex mechanism of OPN in regulating OA and OP is not fully elucidated, which drives us to explore the depth effect of OPN on these two bone diseases.
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Affiliation(s)
- Rui-Jun Bai
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu-Sheng Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
- *Correspondence: Yu-Sheng Li, ; Fang-Jie Zhang,
| | - Fang-Jie Zhang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
- Department of Emergency Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
- *Correspondence: Yu-Sheng Li, ; Fang-Jie Zhang,
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24
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Verdú E, Homs J, Boadas-Vaello P. Physiological Changes and Pathological Pain Associated with Sedentary Lifestyle-Induced Body Systems Fat Accumulation and Their Modulation by Physical Exercise. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:13333. [PMID: 34948944 PMCID: PMC8705491 DOI: 10.3390/ijerph182413333] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/02/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022]
Abstract
A sedentary lifestyle is associated with overweight/obesity, which involves excessive fat body accumulation, triggering structural and functional changes in tissues, organs, and body systems. Research shows that this fat accumulation is responsible for several comorbidities, including cardiovascular, gastrointestinal, and metabolic dysfunctions, as well as pathological pain behaviors. These health concerns are related to the crosstalk between adipose tissue and body systems, leading to pathophysiological changes to the latter. To deal with these health issues, it has been suggested that physical exercise may reverse part of these obesity-related pathologies by modulating the cross talk between the adipose tissue and body systems. In this context, this review was carried out to provide knowledge about (i) the structural and functional changes in tissues, organs, and body systems from accumulation of fat in obesity, emphasizing the crosstalk between fat and body tissues; (ii) the crosstalk between fat and body tissues triggering pain; and (iii) the effects of physical exercise on body tissues and organs in obese and non-obese subjects, and their impact on pathological pain. This information may help one to better understand this crosstalk and the factors involved, and it could be useful in designing more specific training interventions (according to the nature of the comorbidity).
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Affiliation(s)
- Enrique Verdú
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain;
| | - Judit Homs
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain;
- Department of Physical Therapy, EUSES-University of Girona, 17190 Salt, Spain
| | - Pere Boadas-Vaello
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Spain;
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Marcelin G, Clément K. The multifaceted progenitor fates in healthy or unhealthy adipose tissue during obesity. Rev Endocr Metab Disord 2021; 22:1111-1119. [PMID: 34105090 DOI: 10.1007/s11154-021-09662-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/01/2021] [Indexed: 10/21/2022]
Abstract
While obesity is defined as an excessive fat accumulation conferring a risk to metabolic health, increased adipose mass by itself does not fully explain obesity's propensity to promote metabolic alterations. Adipose tissue regulates multiple processes critical for energy homeostasis and its dysfunction favors the development and perpetuation of metabolic diseases. Obesity drives inflammatory leucocyte infiltration in adipose tissue and fibrotic transformation of the fat depots. Both features associate with metabolic alterations such as impaired glucose control and resistance to fat mass loss. In this context, adipose progenitors, an heterogenous resident population of mesenchymal stromal cells, display functions important to shape healthy or unhealthy adipose tissue expansion. We, here, outline the current understanding of adipose progenitor biology in the context of obesity-induced adipose tissue remodeling.
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Affiliation(s)
- Geneviève Marcelin
- Nutrition and Obesities : Systemic Approaches (NutriOmics, UMRS U1269), Sorbonne Universités, INSERM, Paris, France
| | - Karine Clément
- Nutrition and Obesities : Systemic Approaches (NutriOmics, UMRS U1269), Sorbonne Universités, INSERM, Paris, France.
- Nutrition Department, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, CRNH Ile de France, 75013, Paris, France.
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26
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Contenti J, Durand M, Vido S, Declemy S, Raffort J, Carboni J, Bonnet S, Koelsch C, Hassen-Khodja R, Gual P, Mazure NM, Sadaghianloo N. Plasmatic osteopontin and vascular access dysfunction in hemodialysis patients: a cross-sectional, case-control study (The OSMOSIS Study). J Nephrol 2021; 35:527-534. [PMID: 34468976 DOI: 10.1007/s40620-021-01129-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 07/11/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND AIMS Despite close follow-up of patients with native arteriovenous fistulas (AVFs), up to 10% experience thrombosis each year. The OSMOSIS Study (Osteopontin as a Marker of Stenosis) tested the hypothesis that the systemic osteopontin level, a pro-inflammatory mediator related to vascular remodelling and intimal hyperplasia, increases in AVF stenosis, and may be used in clinical surveillance. METHODS Our cross-sectional study compared the level of plasmatic osteopontin (pOPN) between patients with a well-functioning AVF (control group) and patients who required revision of their AVF due to stenosis (stenosis group). Blood samples were collected before dialysis (control group) or before intervention (stenosis group) from the AVF arm, and from the opposite arm as a within-subject control. pOPN level was measured by enzyme-linked immunosorbent assay. RESULTS A total of 76 patients were included in the study. Baseline characteristics were similar between the groups (mean age, 70 years; men, 63%; AVF duration, 39 months), apart from prevalence of type 2 diabetes (T2D) (control group, 33%; stenosis group, 57%; p = 0.04). pOPN levels were similar between the AVF arm and the contralateral arm (551 ± 42 ng/mL vs. 521 ± 41 ng/mL, respectively, p = 0.11, paired t-test). Patients in the stenosis group displayed a higher pOPN level than patients in the control group (650.2 ± 59.8 ng/mL vs. 460.5 ± 61.2, respectively, p = 0.03; two-way ANOVA). T2D was not identified as an associated factor in a multivariate analysis (p = 0.50). CONCLUSIONS The level of pOPN in hemodialysis patients was associated with the presence of AVF stenosis requiring intervention. Thus, its potential as a diagnostic biomarker should be assessed in a vascular access surveillance program.
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Affiliation(s)
- Julie Contenti
- Department of Emergency Medicine, Centre Hospitalier Universitaire de Nice, Nice, France.,Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Université Côte d'Azur, Nice, France
| | - Matthieu Durand
- Department of Urology and Andrology and Renal Transplantation, Centre Hospitalier Universiatire de Nice, Nice, France.,Institute of Research on Cancer and Aging of Nice, INSERM U1081-CNRS, UMR 7284, Université Côte d'Azur, Nice, France
| | - Sandor Vido
- Department of Nephrology and Hemodialysis, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Serge Declemy
- Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, Hôpital Pasteur 1, 30 Ave de la voie Romaine, 06000, Nice, France
| | - Juliette Raffort
- Clinical Chemistry Laboratory (J.R), Centre Hospitalier Universitaire de Nice, Nice, France
| | - Joseph Carboni
- Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, Hôpital Pasteur 1, 30 Ave de la voie Romaine, 06000, Nice, France
| | - Sophie Bonnet
- Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, Hôpital Pasteur 1, 30 Ave de la voie Romaine, 06000, Nice, France.,Department of Clinical Research and Innovation, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Christophe Koelsch
- Department of Anesthesiology, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Réda Hassen-Khodja
- Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Université Côte d'Azur, Nice, France.,Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, Hôpital Pasteur 1, 30 Ave de la voie Romaine, 06000, Nice, France
| | - Philippe Gual
- Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Université Côte d'Azur, Nice, France
| | - Nathalie M Mazure
- Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Université Côte d'Azur, Nice, France
| | - Nirvana Sadaghianloo
- Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Université Côte d'Azur, Nice, France. .,Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, Hôpital Pasteur 1, 30 Ave de la voie Romaine, 06000, Nice, France.
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Larionova I, Kazakova E, Gerashchenko T, Kzhyshkowska J. New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis. Cancers (Basel) 2021; 13:cancers13133253. [PMID: 34209679 PMCID: PMC8268686 DOI: 10.3390/cancers13133253] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Since the targeting of a single pro-angiogenic factor fails to improve oncological disease outcome, significant efforts have been made to identify new pro-angiogenic factors that could compensate for the deficiency of current therapy or act independently as single drugs. Our review aims to present the state-of-the art for well-known and recently described factors produced by macrophages that induce and regulate angiogenesis. A number of positive and negative regulators of angiogenesis in the tumor microenvironment are produced by tumor-associated macrophages (TAMs). Accumulating evidence has indicated that, apart from the well-known angiogenic factors, there are plenty of novel angiogenesis-regulating proteins that belong to different classes. We summarize the data regarding the direct or indirect mechanisms of the interaction of these factors with endothelial cells during angiogenesis. We highlight the recent findings that explain the limitations in the efficiency of current anti-angiogenic therapy approaches. Abstract Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.
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Affiliation(s)
- Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia;
- Correspondence: (I.L.); (J.K.)
| | - Elena Kazakova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
| | - Tatiana Gerashchenko
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia;
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, 68167 Mannheim, Germany
- Correspondence: (I.L.); (J.K.)
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28
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Endocrine role of bone in the regulation of energy metabolism. Bone Res 2021; 9:25. [PMID: 34016950 PMCID: PMC8137703 DOI: 10.1038/s41413-021-00142-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 12/20/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
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Sárvári AK, Van Hauwaert EL, Markussen LK, Gammelmark E, Marcher AB, Ebbesen MF, Nielsen R, Brewer JR, Madsen JGS, Mandrup S. Plasticity of Epididymal Adipose Tissue in Response to Diet-Induced Obesity at Single-Nucleus Resolution. Cell Metab 2021; 33:437-453.e5. [PMID: 33378646 DOI: 10.1016/j.cmet.2020.12.004] [Citation(s) in RCA: 193] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 09/18/2020] [Accepted: 12/04/2020] [Indexed: 12/21/2022]
Abstract
Adipose tissues display a remarkable ability to adapt to the dietary status. Here, we have applied single-nucleus RNA-seq to map the plasticity of mouse epididymal white adipose tissue at single-nucleus resolution in response to high-fat-diet-induced obesity. The single-nucleus approach allowed us to recover all major cell types and to reveal distinct transcriptional stages along the entire adipogenic trajectory from preadipocyte commitment to mature adipocytes. We demonstrate the existence of different adipocyte subpopulations and show that obesity leads to disappearance of the lipogenic subpopulation and increased abundance of the stressed lipid-scavenging subpopulation. Moreover, obesity is associated with major changes in the abundance and gene expression of other cell populations, including a dramatic increase in lipid-handling genes in macrophages at the expense of macrophage-specific genes. The data provide a powerful resource for future hypothesis-driven investigations of the mechanisms of adipocyte differentiation and adipose tissue plasticity.
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Affiliation(s)
- Anitta Kinga Sárvári
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Elvira Laila Van Hauwaert
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Lasse Kruse Markussen
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Ellen Gammelmark
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Ann-Britt Marcher
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Morten Frendø Ebbesen
- Danish Molecular Biomedical Imaging Center, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Ronni Nielsen
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Jonathan Richard Brewer
- Danish Molecular Biomedical Imaging Center, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark
| | - Jesper Grud Skat Madsen
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark.
| | - Susanne Mandrup
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark.
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30
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Dai Y, Pracana R, Holland PWH. Divergent genes in gerbils: prevalence, relation to GC-biased substitution, and phenotypic relevance. BMC Evol Biol 2020; 20:134. [PMID: 33076817 PMCID: PMC7574485 DOI: 10.1186/s12862-020-01696-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/29/2020] [Indexed: 11/25/2022] Open
Abstract
Background Two gerbil species, sand rat (Psammomys obesus) and Mongolian jird (Meriones unguiculatus), can become obese and show signs of metabolic dysregulation when maintained on standard laboratory diets. The genetic basis of this phenotype is unknown. Recently, genome sequencing has uncovered very unusual regions of high guanine and cytosine (GC) content scattered across the sand rat genome, most likely generated by extreme and localized biased gene conversion. A key pancreatic transcription factor PDX1 is encoded by a gene in the most extreme GC-rich region, is remarkably divergent and exhibits altered biochemical properties. Here, we ask if gerbils have proteins in addition to PDX1 that are aberrantly divergent in amino acid sequence, whether they have also become divergent due to GC-biased nucleotide changes, and whether these proteins could plausibly be connected to metabolic dysfunction exhibited by gerbils. Results We analyzed ~ 10,000 proteins with 1-to-1 orthologues in human and rodents and identified 50 proteins that accumulated unusually high levels of amino acid change in the sand rat and 41 in Mongolian jird. We show that more than half of the aberrantly divergent proteins are associated with GC biased nucleotide change and many are in previously defined high GC regions. We highlight four aberrantly divergent gerbil proteins, PDX1, INSR, MEDAG and SPP1, that may plausibly be associated with dietary metabolism. Conclusions We show that through the course of gerbil evolution, many aberrantly divergent proteins have accumulated in the gerbil lineage, and GC-biased nucleotide substitution rather than positive selection is the likely cause of extreme divergence in more than half of these. Some proteins carry putatively deleterious changes that could be associated with metabolic and physiological phenotypes observed in some gerbil species. We propose that these animals provide a useful model to study the ‘tug-of-war’ between natural selection and the excessive accumulation of deleterious substitutions mutations through biased gene conversion.
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Affiliation(s)
- Yichen Dai
- Department of Zoology, University of Oxford, 11a Mansfield Road, Oxford, OX1 3SZ, UK
| | - Rodrigo Pracana
- Department of Zoology, University of Oxford, 11a Mansfield Road, Oxford, OX1 3SZ, UK
| | - Peter W H Holland
- Department of Zoology, University of Oxford, 11a Mansfield Road, Oxford, OX1 3SZ, UK.
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Ezzati-Mobaser S, Malekpour-Dehkordi Z, Nourbakhsh M, Tavakoli-Yaraki M, Ahmadpour F, Golpour P, Nourbakhsh M. The up-regulation of markers of adipose tissue fibrosis by visfatin in pre-adipocytes as well as obese children and adolescents. Cytokine 2020; 134:155193. [PMID: 32707422 DOI: 10.1016/j.cyto.2020.155193] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 06/25/2020] [Accepted: 07/04/2020] [Indexed: 01/01/2023]
Abstract
Adipocytes are surrounded by a three-dimensional network of extracellular matrix (ECM) proteins. Aberrant ECM accumulation and remodeling leads to adipose tissue fibrosis. Visfatin is one of the adipocytokines that is increased in obesity and is implicated in insulin resistance. The objective of this study was to investigate the effect of visfatin on major components of ECM remodeling. In this study, plasma levels of both endotrophin and visfatin in obese children and adolescents were significantly higher than those in control subjects and they showed a positive correlation with each other. Treatment of 3T3-L1 pre-adipocytes with visfatin caused significant up-regulation of Osteopontin (Opn), Collagen type VI (Col6), matrix metalloproteinases MMP-2 and MMP-9. By using inhibitors of major signaling pathways it was shown that visfatin exerted its effect on Col6a3 gene expression through PI3K, JNK, and NF-кB pathways, while induced Opn gene expression via PI3K, JNK, MAPK/ERK, and NOTCH1. Our conclusion is that, the relationship between visfatin, endotrophin and insulin resistance parameters in obesity as well as increased expression of ECM proteins by visfatin suggests adipose tissue fibrosis as a mechanism for devastating effects of visfatin in obesity.
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Affiliation(s)
- Samira Ezzati-Mobaser
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Malekpour-Dehkordi
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mona Nourbakhsh
- Hazrat Aliasghar Children's Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ahmadpour
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Pegah Golpour
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mitra Nourbakhsh
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Osteopontin: The Molecular Bridge between Fat and Cardiac-Renal Disorders. Int J Mol Sci 2020; 21:ijms21155568. [PMID: 32759639 PMCID: PMC7432729 DOI: 10.3390/ijms21155568] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/30/2020] [Accepted: 08/01/2020] [Indexed: 12/12/2022] Open
Abstract
Osteopontin (OPN) is a multifaceted matricellular protein, with well-recognized roles in both the physiological and pathological processes in the body. OPN is expressed in the main organs and cell types, in which it induces different biological actions. During physiological conditioning, OPN acts as both an intracellular protein and soluble excreted cytokine, regulating tissue remodeling and immune-infiltrate in adipose tissue the heart and the kidney. In contrast, the increased expression of OPN has been correlated with the severity of the cardiovascular and renal outcomes associated with obesity. Indeed, OPN expression is at the “cross roads” of visceral fat extension, cardiovascular diseases (CVDs) and renal disorders, in which OPN orchestrates the molecular interactions, leading to chronic low-grade inflammation. The common factor associated with OPN overexpression in adipose, cardiac and renal tissues seems attributable to the concomitant increase in visceral fat size and the increase in infiltrated OPN+ macrophages. This review underlines the current knowledge on the molecular interactions between obesity and the cardiac–renal disorders ruled by OPN.
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Onogi Y, Khalil AEMM, Ussar S. Identification and characterization of adipose surface epitopes. Biochem J 2020; 477:2509-2541. [PMID: 32648930 PMCID: PMC7360119 DOI: 10.1042/bcj20190462] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/14/2022]
Abstract
Adipose tissue is a central regulator of metabolism and an important pharmacological target to treat the metabolic consequences of obesity, such as insulin resistance and dyslipidemia. Among the various cellular compartments, the adipocyte cell surface is especially appealing as a drug target as it contains various proteins that when activated or inhibited promote adipocyte health, change its endocrine function and eventually maintain or restore whole-body insulin sensitivity. In addition, cell surface proteins are readily accessible by various drug classes. However, targeting individual cell surface proteins in adipocytes has been difficult due to important functions of these proteins outside adipose tissue, raising various safety concerns. Thus, one of the biggest challenges is the lack of adipose selective surface proteins and/or targeting reagents. Here, we discuss several receptor families with an important function in adipogenesis and mature adipocytes to highlight the complexity at the cell surface and illustrate the problems with identifying adipose selective proteins. We then discuss that, while no unique adipocyte surface protein might exist, how splicing, posttranslational modifications as well as protein/protein interactions can create enormous diversity at the cell surface that vastly expands the space of potentially unique epitopes and how these selective epitopes can be identified and targeted.
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Affiliation(s)
- Yasuhiro Onogi
- RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Ahmed Elagamy Mohamed Mahmoud Khalil
- RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Siegfried Ussar
- RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
- Department of Medicine, Technische Universität München, Munich, Germany
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Nasias D, Dalakoura-Karagkouni K, Vassou D, Papagiannakis G, Papadaki A, Kardassis D. Transcriptome analysis of the adipose tissue in a mouse model of metabolic syndrome identifies gene signatures related to disease pathogenesis. Genomics 2020; 112:4053-4062. [PMID: 32652102 DOI: 10.1016/j.ygeno.2020.06.053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 06/12/2020] [Accepted: 06/29/2020] [Indexed: 12/14/2022]
Abstract
The white adipose tissue (WAT) contributes to the metabolic imbalance observed in obesity and the metabolic syndrome (MetS) by mechanisms that are poorly understood. The aim of this study was to monitor changes in the transcriptome of epididymal WAT during the development of MetS. ApoE3L.CETP mice were fed a high fat (HFD) or a low-fat (LFD) diet for different time periods. Adipose RNA was analyzed by microarrays. We found an increasing number of differentially expressed transcripts during MetS development. In mice with MetS, 1396 transcripts were differentially expressed including transcripts related to immune/inflammatory responses and extracellular matrix enzymes, suggesting significant inflammation and tissue remodeling. The top list of pathways included focal adhesion, chemokine, B and T cell receptor and MAPK signaling. The data identify for the first time adipose gene signatures in apoE3L.CETP mice with diet-induced MetS and might open new avenues for investigation of potential biomarkers or therapeutic targets.
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Affiliation(s)
- Dimitris Nasias
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion 71003, Greece; Gene Regulation and Epigenetics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion 70013, Greece
| | - Katerina Dalakoura-Karagkouni
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion 71003, Greece; Gene Regulation and Epigenetics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion 70013, Greece
| | - Despoina Vassou
- Genomics Facility, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion 70013, Greece
| | - Giorgos Papagiannakis
- Genomics Facility, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion 70013, Greece
| | - Ariadni Papadaki
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion 71003, Greece
| | - Dimitris Kardassis
- Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion 71003, Greece; Gene Regulation and Epigenetics group, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion 70013, Greece.
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Nardo AD, Grün NG, Zeyda M, Dumanic M, Oberhuber G, Rivelles E, Helbich TH, Markgraf DF, Roden M, Claudel T, Trauner M, Stulnig TM. Impact of osteopontin on the development of non-alcoholic liver disease and related hepatocellular carcinoma. Liver Int 2020; 40:1620-1633. [PMID: 32281248 PMCID: PMC7384114 DOI: 10.1111/liv.14464] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/14/2020] [Accepted: 03/31/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Osteopontin, a multifunctional protein and inflammatory cytokine, is overexpressed in adipose tissue and liver in obesity and contributes to the induction of adipose tissue inflammation and non-alcoholic fatty liver (NAFL). Studies performed in both mice and humans also point to a potential role for OPN in malignant transformation and tumour growth. To fully understand the role of OPN on the development of NAFL-derived hepatocellular carcinoma (HCC), we applied a non-alcoholic steatohepatitis (NASH)-HCC mouse model on osteopontin-deficient (Spp1-/- ) mice analysing time points of NASH, fibrosis and HCC compared to wild-type mice. METHODS Two-day-old wild-type and Spp1-/- mice received a low-dose streptozotocin injection in order to induce diabetes, and were fed a high-fat diet starting from week 4. Different cohorts of mice of both genotypes were sacrificed at 8, 12 and 19 weeks of age to evaluate the NASH, fibrosis and HCC phenotypes respectively. RESULTS Spp1-/- animals showed enhanced hepatic lipid accumulation and aggravated NASH, as also increased hepatocellular apoptosis and accelerated fibrosis. The worse steatotic and fibrotic phenotypes observed in Spp1-/- mice might be driven by enhanced hepatic fatty acid influx through CD36 overexpression and by a pathological accumulation of specific diacylglycerol species during NAFL. Lack of osteopontin lowered systemic inflammation, prevented HCC progression to less differentiated tumours and improved overall survival. CONCLUSIONS Lack of osteopontin dissociates NASH-fibrosis severity from overall survival and HCC malignant transformation in NAFLD, and is therefore a putative therapeutic target only for advanced chronic liver disease.
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Affiliation(s)
- Alexander D. Nardo
- Christian Doppler Laboratory for Cardio‐Metabolic Immunotherapy and Clinical Division of Endocrinology and MetabolismDepartment of Medicine IIIMedical University of ViennaViennaAustria,Present address:
Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology & HepatologyMedical University of ViennaVienna1090Austria
| | - Nicole G. Grün
- Christian Doppler Laboratory for Cardio‐Metabolic Immunotherapy and Clinical Division of Endocrinology and MetabolismDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Maximilian Zeyda
- Christian Doppler Laboratory for Cardio‐Metabolic Immunotherapy and Clinical Division of Endocrinology and MetabolismDepartment of Medicine IIIMedical University of ViennaViennaAustria,Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
| | - Monika Dumanic
- Division of Nuclear MedicineDepartment of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria
| | - Georg Oberhuber
- Department of PathologyGeneral Hospital of InnsbruckInnsbruckAustria
| | - Elisa Rivelles
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Thomas H. Helbich
- Division of Nuclear MedicineDepartment of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria,Division of Molecular and Gender ImagingDepartment of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria
| | - Daniel F. Markgraf
- German Diabetes CenterLeibniz Center for Diabetes ResearchInstitute for Clinical DiabetologyHeinrich Heine UniversityDüsseldorfGermany
| | - Michael Roden
- German Diabetes CenterLeibniz Center for Diabetes ResearchInstitute for Clinical DiabetologyHeinrich Heine UniversityDüsseldorfGermany,German Center of Diabetes Research (DZD e.V.)München‐NeuherbergGermany,Division of Endocrinology and DiabetologyMedical FacultyHeinrich‐Heine UniversityDüsseldorfGermany
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology & HepatologyMedical University of ViennaViennaAustria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology & HepatologyMedical University of ViennaViennaAustria
| | - Thomas M. Stulnig
- Christian Doppler Laboratory for Cardio‐Metabolic Immunotherapy and Clinical Division of Endocrinology and MetabolismDepartment of Medicine IIIMedical University of ViennaViennaAustria,Present address:
Third Department of Medicine and Karl Landsteiner Institute for Metabolic Diseases and NephrologyHietzing HospitalVienna1130Austria
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A high-fat diet rich in corn oil exaggerates the infarct size and memory impairment in rats with cerebral ischemia and is associated with suppressing osteopontin and Akt, and activating GS3Kβ, iNOS, and NF-κB. J Physiol Biochem 2020; 76:393-406. [PMID: 32488539 DOI: 10.1007/s13105-020-00744-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 05/01/2020] [Indexed: 01/04/2023]
Abstract
The increase in osteopontin (OPN) levels after stroke induces neural protection by activating Akt signaling and inhibiting GS3Kβ, iNOS, and NF-κB. This study investigated the effect of a high-fat diet rich in corn oil (CO-HFD) on infarct size and memory function in rats after induction of cerebral ischemia in rats and investigated its effect on the expression of OPN/Akt/iNOS/NF-κB signaling pathways. Rats were initially fed a standard diet (STD, 3.82 kcal/g; 9.4%, from fat) or a CO-HFD (5.4 kcal/g, 40% from fat) for 12 weeks. Then, both groups were further subdivided into either sham group or group exposed to cerebral ischemia by the middle cerebral artery occlusion (MCAO) protocol. Compared with sham-operated rats fed STD diet, neurological scores and both short- and long-term memory functions were significantly impaired in sham-operated CO-HFD-fed rats. In addition, brains collected from CO-HFD-fed rats showed lower protein levels of OPN, p-Akt (Thr308), p-GS3Kβ (Ser9), and Bcl-2 and had higher protein levels of iNOS, cleaved caspase-3, nuclear NF-κB p65, and cytoplasmic cytochrome C. However, once exposed to MCAO surgery, similar but more profound alterations of all these biochemical parameters with more severe impairment in short- and long-term memory functions and larger infarct size were noticed in the brains of CO-HFD-fed rats as compared with STD-fed rats exposed to MCAO. In conclusion, chronic consumption of CO-HFD induces memory impairments and worsens memory function recovery and infarct size after cerebral ischemia in rats by reducing levels of OPN, inhibiting the activation of Akt and activating iNOS and NF-κB.
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The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat Commun 2020; 11:2482. [PMID: 32424156 PMCID: PMC7235045 DOI: 10.1038/s41467-020-16347-w] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/22/2020] [Indexed: 12/26/2022] Open
Abstract
Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction. Senescent T cells, defined as CD4+ CD44high CD62Llow PD-1+ CD153+ cells, accumulate in visceral adipose tissues (VAT) in obese individuals. Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with Alhydrogel (CD153-Alum) or CpG oligodeoxynucleotide (ODN) 1585 (CD153-CpG) and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10–11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of CD153-CpG-vaccinated mice, accompanied by glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the CD153-CpG-vaccinated mice successfully reduced the number of senescent T cells. The CD153-CpG vaccine is an optional tool for senolytic therapy. Senotherapy, the removal of aged T cells, is an effective approach to attenuate age-related diseases. Here the authors report a CD153 targeting vaccine that prevents the accumulation of senescent adipose tissue T cells in mice on high-fat diet, which is associated with improved glucose tolerance.
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Lu Y, Xu Y, Yuan W, Wang M, Zhou Y, Chen K, Huang Q. Downregulation of osteopontin inhibits browning of white adipose tissues through PI3K-AKT pathway in C57BL / 6 mice. Eur J Pharmacol 2020; 866:172822. [PMID: 31760068 DOI: 10.1016/j.ejphar.2019.172822] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 10/25/2022]
Abstract
Brown adipose tissue (BAT) plays important roles in regulating energy homeostasis and combating obesity. Accordingly, increasing the abundance and/or activating BAT would be effective and promising approaches to combat obesity and obesity-relative diseases. Our previous data in vitro have shown that osteopontin (OPN) induces the brown adipogenesis in 3T3-L1 cells via a phosphatidylinositol 3 kinase (PI3K)-AKT pathway. However, it is currently unknown whether OPN exerts such an effect on animals in vivo. Therefore, in the study we sought to investigate the pro-browning effects of OPN and to explore its underlying mechanisms by transfecting with Ad-GFP-aP2-OPN-shRNA to specifically down-regulate the OPN of white adipose tissue (WAT) in mice. Our present results show that downregulation of OPN in WAT exacerbates obesity and inhibits WAT-browning. Moreover, immunohistochemical results also exhibit that the downregulation of OPN significantly diminishes the expression and sub-cellular localization of UCP-1, PRDM16 and PGC-1α. Besides, the western blotting results reveal that the expression levels of PI3K, AKT-pS473 and PPARγ markedly reduce. Consequently, we conclude that the downregulation of OPN inhibits the browning of WAT through inhibiting the expression of PPARγ mediated by the PI3K-AKT pathway. The findings suggest that OPN is involved in regulation of WAT-browning and regulating its expression would become a potential strategy to combat obesity and obesity-relative metabolic diseases.
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Affiliation(s)
- Yi Lu
- Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China; Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Yuhong Xu
- The First Clinical Medical School, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Wanwan Yuan
- Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China; Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Mengxi Wang
- Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China; Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Yumeng Zhou
- Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China; Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Kai Chen
- Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China; Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Qiren Huang
- Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China; Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, Jiangxi Province, PR China.
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Wang C, He M, Peng J, Li S, Long M, Chen W, Liu D, Yang G, Zhang L. Increased plasma osteopontin levels are associated with nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Cytokine 2020; 125:154837. [PMID: 31514105 DOI: 10.1016/j.cyto.2019.154837] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/27/2019] [Accepted: 09/03/2019] [Indexed: 12/29/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) commonly occurs in patients with type 2 diabetes mellitus (T2DM). Osteopontin (OPN) is a multifunctional protein with pleiotropic physiological functions. This study aimed to investigate the interrelation between circulating OPN and NAFLD in T2DM patients. Overall, 249 subjects were classified into 4 groups: 53 patients with NAFLD and T2DM; 57 with newly diagnosed T2DM; 59 with NAFLD; and 80 healthy age- and sex-matched controls. Serum OPN was measured by ELISA. The OPN distribution in the pooled data was divided into quartiles; significant trends across increasing quartiles were estimated by the Cochran-Armitage trend test. Compared with the controls, circulating OPN concentrations were significantly elevated in NAFLD patients and T2DM patients with or without NAFLD. Serum OPN levels were higher in the overweight/obese group than that in the lean group. Circulating OPN levels were positively correlated with CRP, age, BMI, SBP, DBP, HbA1c, UA, TGs, WBCs, neutrophils, FBG, and HOMA-IR and negatively correlated with ADP, albumin and HDL. Age, albumin, HbA1c, HDL and hsCRP were independently related to circulating OPN. The relative risks for NAFLD, T2DM and T2DM with NAFLD increased significantly along with increasing OPN quartiles based on the Cochran-Armitage trend test. OPN is an optimal predictor in the diagnosis of T2DM with NAFLD and T2DM and may contribute to the aggravation of the metabolic state.
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Affiliation(s)
- Cong Wang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Miao He
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Jiajia Peng
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Shengbing Li
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Min Long
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Wenwen Chen
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Dongfang Liu
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Gangyi Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Lili Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China.
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Wu J, Wu D, Zhang L, Lin C, Liao J, Xie R, Li Z, Wu S, Liu A, Hu W, Xi Y, Bu S, Wang F. NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production. J Leukoc Biol 2019; 107:589-596. [PMID: 31829469 DOI: 10.1002/jlb.3ma1119-173r] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 12/21/2022] Open
Abstract
High-fat diet (HFD) induced hepatic endoplasmic reticulum (ER) stress drives insulin resistance (IR) and steatosis. NK cells in adipose tissue play an important role in the pathogenesis of IR in obesity. Whether NK cells in the liver can induce hepatic ER stress and thus promote IR in obesity is still unknown. We demonstrate that HFD-fed mice display elevated production of proinflammatory cytokine osteopontin (OPN) in hepatic NK cells, especially in CD49a+ DX5- tissue-resident NK (trNK) cells. Obesity-induced ER stress, IR, and steatosis in the liver are ameliorated by ablating NK cells with neutralizing antibody in HFD-fed mice. OPN treatment enhances the expression of ER stress markers, including p-PERK, p-eIF2, ATF4, and CHOP in both murine liver tissues and HL-7702, a human liver cell line. Pretreatment of HL-7702 cells with OPN promotes hyperactivation of JNK and subsequent decrease of tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), resulting in impaired insulin signaling, which can be reversed by inhibiting ER stress. Collectively, we demonstrate that hepatic NK cells induce obesity-induced hepatic ER stress, and IR through OPN production.
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Affiliation(s)
- Junhua Wu
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China.,Ningbo Women and Children's Hospital, Ningbo, China
| | - Danyang Wu
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Longyao Zhang
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Chuxuan Lin
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Jiahao Liao
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Ruyin Xie
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Zhulin Li
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Siyang Wu
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Aimin Liu
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Weining Hu
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Yang Xi
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Shizhong Bu
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
| | - Fuyan Wang
- Diabetes Research Center, Medical School of Ningbo University, Ningbo, China
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Hasib A, Hennayake CK, Bracy DP, Bugler-Lamb AR, Lantier L, Khan F, Ashford MLJ, McCrimmon RJ, Wasserman DH, Kang L. CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice. Am J Physiol Endocrinol Metab 2019; 317:E973-E983. [PMID: 31550181 PMCID: PMC6957377 DOI: 10.1152/ajpendo.00215.2019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient (cd44-/-) mice and wild-type littermates (cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44-/- mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44-/- mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44-/- mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44-/- compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44-/- mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44-/- mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.
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Affiliation(s)
- Annie Hasib
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Chandani K Hennayake
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Deanna P Bracy
- Department of Molecular Physiology and Biophysics and Mouse Metabolic Phenotyping Centre, Vanderbilt University, Nashville, Tennessee
| | - Aimée R Bugler-Lamb
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Louise Lantier
- Department of Molecular Physiology and Biophysics and Mouse Metabolic Phenotyping Centre, Vanderbilt University, Nashville, Tennessee
| | - Faisel Khan
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Michael L J Ashford
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Rory J McCrimmon
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - David H Wasserman
- Department of Molecular Physiology and Biophysics and Mouse Metabolic Phenotyping Centre, Vanderbilt University, Nashville, Tennessee
| | - Li Kang
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
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Landecho MF, Tuero C, Valentí V, Bilbao I, de la Higuera M, Frühbeck G. Relevance of Leptin and Other Adipokines in Obesity-Associated Cardiovascular Risk. Nutrients 2019; 11:nu11112664. [PMID: 31694146 PMCID: PMC6893824 DOI: 10.3390/nu11112664] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/02/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023] Open
Abstract
Obesity, which is a worldwide epidemic, confers increased risk for multiple serious conditions including type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue only for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins, and growth and vasoactive factors, which are collectively called adipokines known to influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. This review describes the relevance of specific adipokines in the obesity-associated cardiovascular disease.
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Affiliation(s)
- Manuel F. Landecho
- Department of Internal Medicine, General Health Check-up Unit, Clínica Universidad de Navarra, Avenida Pío XII, 36, 31008 Pamplona, Navarra, Spain; (M.F.L.); (I.B.)
| | - Carlota Tuero
- Department of Surgery, Bariatric and Metabolic Surgery Unit, Clínica Universidad de Navarra, 31008 Pamplona, Navarra, Spain; (C.T.); (V.V.)
| | - Víctor Valentí
- Department of Surgery, Bariatric and Metabolic Surgery Unit, Clínica Universidad de Navarra, 31008 Pamplona, Navarra, Spain; (C.T.); (V.V.)
- Instituto de Salud Carlos III, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 31008 Pamplona, Navarra, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Navarra, Spain
| | - Idoia Bilbao
- Department of Internal Medicine, General Health Check-up Unit, Clínica Universidad de Navarra, Avenida Pío XII, 36, 31008 Pamplona, Navarra, Spain; (M.F.L.); (I.B.)
| | - Magdalena de la Higuera
- Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, 28027 Madrid, Spain;
| | - Gema Frühbeck
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Navarra, Spain
- Metabolic Research Laboratory, Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Pamplona, Spain
- Correspondence: ; Tel.: +0034-948-255-400
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Yakaiah V, Dakshinamoorthi A, Kavimani S. Effect of Myristica fragrans extract on total body composition in cafeteria diet induced obese rats. Bioinformation 2019; 15:657-665. [PMID: 31787815 PMCID: PMC6859705 DOI: 10.6026/97320630015657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/07/2019] [Accepted: 10/09/2019] [Indexed: 12/04/2022] Open
Abstract
It is of interest to evaluate the effect of Myristica fragrans on body composition of cafeteria diet induced obese rats. Thirty rats (150-160g) grouped into 5 and each group contains 6 rats. Group-1 was normal control and 2-5 groups were fed with cafeteria diet for 15 weeks to induce obesity. From 16th week to 25th week test drugs were given as mentioned in the experimental protocol. Body weight, BMI, changes in body composition was measured by TOBEC, adipose tissue weights, organ weights, abdominal circumference were measured according to standard methods. After 70days of treatment with MFE 200mg/kg, 400mg/kg Body weight reduced by 9.29%, 12.87% respectively. BMI was also decreased. Abdominal circumference, total fat percentage, organ weights, was substantially reduced. At 400mg/kg of MFE has shown maximum potentiality when compared with 200mg/kg. Orlistat 50mg was used as standard drug. Tetrahydrofuran, flavonoids, saponins, present in Myristica fragrans has shown anti obesity activity. Our findings explain the potentiality of phytochemicals as a potent anti obesity agent, provide scientific evidence for its traditional use and suggest the possible mechanism of action.
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Affiliation(s)
| | | | - Subramanian Kavimani
- Mother Theresa Post Graduate and Research Institute of Health Sciences, Pondicherry
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Ruiz-Ojeda FJ, Méndez-Gutiérrez A, Aguilera CM, Plaza-Díaz J. Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases. Int J Mol Sci 2019; 20:4888. [PMID: 31581657 PMCID: PMC6801592 DOI: 10.3390/ijms20194888] [Citation(s) in RCA: 169] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 09/25/2019] [Accepted: 09/29/2019] [Indexed: 12/15/2022] Open
Abstract
The extracellular matrix (ECM) is a network of different proteins and proteoglycans that controls differentiation, migration, repair, survival, and development, and it seems that its remodeling is required for healthy adipose tissue expansion. Obesity drives an excessive lipid accumulation in adipocytes, which provokes immune cells infiltration, fibrosis (an excess of deposition of ECM components such as collagens, elastin, and fibronectin) and inflammation, considered a consequence of local hypoxia, and ultimately insulin resistance. To understand the mechanism of this process is a challenge to treat the metabolic diseases. This review is focused at identifying the putative role of ECM in adipose tissue, describing its structure and components, its main tissue receptors, and how it is affected in obesity, and subsequently the importance of an appropriate ECM remodeling in adipose tissue expansion to prevent metabolic diseases.
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Affiliation(s)
- Francisco Javier Ruiz-Ojeda
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain.
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain.
- RG Adipocytes and metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Center Munich, 85764 Neuherberg, Munich, Germany.
| | - Andrea Méndez-Gutiérrez
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain.
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain.
- Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n. 18016 Armilla, Granada, Spain.
- CIBEROBN (CIBER Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Concepción María Aguilera
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain.
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain.
- Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n. 18016 Armilla, Granada, Spain.
- CIBEROBN (CIBER Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Julio Plaza-Díaz
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain.
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain.
- Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n. 18016 Armilla, Granada, Spain.
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Fitter S, Zannettino ACW. Osteopontin in the pathophysiology of obesity: Is Opn a fat cell foe? Obes Res Clin Pract 2019; 12:249-250. [PMID: 29914635 DOI: 10.1016/j.orcp.2018.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Stephen Fitter
- Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide and the Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
| | - Andrew C W Zannettino
- Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide and the Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
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Wanko B, Tardelli M, Jürets A, Neuhofer A, Prager G, Morser J, Leung LL, Staffler G, Zeyda M, Stulnig TM. Antibody-mediated targeting of cleavage-specific OPN-T cell interactions. PLoS One 2019; 14:e0214938. [PMID: 30951532 PMCID: PMC6450625 DOI: 10.1371/journal.pone.0214938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 03/22/2019] [Indexed: 12/21/2022] Open
Abstract
T cells are crucial players in obesity-mediated adipose tissue inflammation. We hypothesized that osteopontin (OPN), an inflammatory protein with enhanced activity when proteolytically cleaved, affects the number of viable T cells in adipose tissue and assessed inhibition of the interaction between T cells and thrombin and matrix metalloproteinases-cleaved OPN using antibodies and postimmune sera. Gene expression of T cell markers in adipose tissue from wild-type (wt) and Spp1-/- (OPN deficient) mice was analyzed after 16 weeks of high fat diet (HFD) or low fat diet (LFD) feeding. CD3, CD8 and OPN gene expression in omental adipose tissue from individuals with obesity was measured. OPN-T cell interactions were assessed with a fluorescence-based adhesion assay and blocked with antibodies targeting OPN. Comparison of T cell gene expression in adipose tissue from wt and Spp1-/- mice showed that OPN affected the number of T cells while in humans, levels of OPN correlated with T cell markers in omental adipose tissue. The interaction between T cells and cleaved OPN was blocked by postimmune sera following OPN peptide vaccinations and with monoclonal antibodies. In conclusion, levels of OPN affected the number of T cells in obesity and antibodies against cleaved OPN antagonize OPN-T cell interactions.
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Affiliation(s)
- Bettina Wanko
- Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna, Vienna, Austria
- Division of Hematology, Stanford University School of Medicine, Stanford, California, United States of America
- Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America
| | - Matteo Tardelli
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alexander Jürets
- Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna, Vienna, Austria
| | - Angelika Neuhofer
- Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna, Vienna, Austria
| | - Gerhard Prager
- Department of Surgery, Medical University Vienna, Vienna, Austria
| | - John Morser
- Division of Hematology, Stanford University School of Medicine, Stanford, California, United States of America
- Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America
| | - Lawrence L. Leung
- Division of Hematology, Stanford University School of Medicine, Stanford, California, United States of America
- Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America
| | | | - Maximilian Zeyda
- Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna, Vienna, Austria
| | - Thomas M. Stulnig
- Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna, Vienna, Austria
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Ali Khan A, Hansson J, Weber P, Foehr S, Krijgsveld J, Herzig S, Scheideler M. Comparative Secretome Analyses of Primary Murine White and Brown Adipocytes Reveal Novel Adipokines. Mol Cell Proteomics 2018; 17:2358-2370. [PMID: 30135203 PMCID: PMC6283297 DOI: 10.1074/mcp.ra118.000704] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 08/06/2018] [Indexed: 12/13/2022] Open
Abstract
The adipose organ, including white and brown adipose tissues, is an important player in systemic energy homeostasis, storing excess energy in form of lipids while releasing energy upon various energy demands. Recent studies have demonstrated that white and brown adipocytes also function as endocrine cells and regulate systemic metabolism by secreting factors that act locally and systemically. However, a comparative proteomic analysis of secreted factors from white and brown adipocytes and their responsiveness to adrenergic stimulation has not been reported yet. Therefore, we studied and compared the secretome of white and brown adipocytes, with and without norepinephrine (NE) stimulation. Our results reveal that carbohydrate-metabolism-regulating proteins are preferably secreted from white adipocytes, while brown adipocytes predominantly secrete a large variety of proteins. Upon NE stimulation, an increased secretion of known adipokines is favored by white adipocytes while brown adipocytes secreted higher amounts of novel adipokines. Furthermore, the secretory response between NE-stimulated and basal state was multifaceted addressing lipid and glucose metabolism, adipogenesis, and antioxidative reactions. Intriguingly, NE stimulation drastically changed the secretome in brown adipocytes. In conclusion, our study provides a comprehensive catalogue of novel adipokine candidates secreted from white and brown adipocytes with many of them responsive to NE. Given the beneficial effects of brown adipose tissue activation on its endocrine function and systemic metabolism, this study provides an archive of novel batokine candidates and biomarkers for activated brown adipose tissue.
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Affiliation(s)
- Asrar Ali Khan
- Institute for Diabetes and Cancer (IDC); Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jenny Hansson
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Peter Weber
- Institute for Diabetes and Cancer (IDC); Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Sophia Foehr
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen Krijgsveld
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephan Herzig
- Institute for Diabetes and Cancer (IDC); Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Marcel Scheideler
- Institute for Diabetes and Cancer (IDC); Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany; Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
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Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem 2018; 59:17-24. [PMID: 30003880 DOI: 10.1016/j.clinbiochem.2018.07.003] [Citation(s) in RCA: 392] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/03/2018] [Accepted: 07/08/2018] [Indexed: 12/12/2022]
Abstract
Osteopontin (OPN) is a highly phosphorylated glycophosphoprotein having acidic characteristics and rich in aspartic acid. OPN, a multifunctional protein, has important functions on cardiovascular diseases, cancer, diabetes and kidney stone diseases and in the process of inflammation, biomineralization, cell viability and wound healing. Osteopontin acts on organisms by playing a key role in secretion levels of interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-3 (IL-3), interferon-γ (IFN-γ), integrin αvB3, nuclear factor kappa B (NF-kB), macrophage and T cells, regulating the osteoclast function and affecting CD44 receptors. The aim of the present review is to address majority of different functions of OPN protein which are known, suspected or suggested through the data obtained about this protein yet.
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Affiliation(s)
- Mehmet Arif Icer
- Gazi University, Faculty of Health Sciences, Nutrition and Dietetics Department, 06500 Beşevler, Ankara, Turkey.
| | - Makbule Gezmen-Karadag
- Gazi University, Faculty of Health Sciences, Nutrition and Dietetics Department, 06500 Beşevler, Ankara, Turkey.
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Choe EK, Yi JW, Chai YJ, Park KJ. Upregulation of the adipokine genes ADIPOR1 and SPP1 is related to poor survival outcomes in colorectal cancer. J Surg Oncol 2018; 117:1833-1840. [DOI: 10.1002/jso.25078] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 03/29/2018] [Indexed: 12/22/2022]
Affiliation(s)
- Eun K. Choe
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
- Department of Surgery; Seoul National University Hospital Healthcare System Gangnam Center; Seoul Korea
| | - Jin W. Yi
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
| | - Young J. Chai
- Department of Surgery; Seoul National University Boramae Medical Center; Seoul Korea
| | - Kyu J. Park
- Department of Surgery; Seoul National University College of Medicine; Seoul Korea
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Özdemir ZC, Düzenli Kar Y, Demiral M, Sırmagül B, Bör Ö, Kırel B. The Frequency of Metabolic Syndrome and Serum Osteopontin Levels in Survivors of Childhood Acute Lymphoblastic Leukemia. J Adolesc Young Adult Oncol 2018; 7:480-487. [PMID: 29641359 DOI: 10.1089/jayao.2017.0129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Metabolic syndrome (MetS) and obesity have increasingly been reported in survivors of childhood cancer. Osteopontin (OPN) is primarily synthesized in adipose tissue and is thought to have a role in obesity and the development of insulin resistance (IR). The aim of this study was to investigate the frequency of MetS in survivors of acute lymphoblastic leukemia (ALL) and to establish the relationship between serum OPN levels and anthropometric measurements and glucose metabolism. METHODS A total 50 survivors of ALL (median age: 10.5 years; post-treatment interval 4.54 ± 2.48 years), and 20 healthy children (median age: 11 years) were included in the study. Anthropometric measurements were taken, and serum glucose, insulin, homeostasis model assessment and IR index (HOMA-IR index), lipoprotein, thyroid hormone levels, and OPN levels were measured. RESULTS Twenty-one (42%) survivors were overweight/obese, 2 (5.1%) survivors had MetS, 7 (14%) survivors had IR, and 19 (38%) survivors had dyslipidemia. Fasting insulin levels and HOMA-IR of the overweight/obese survivors were significantly higher than those of the normal-weight survivors (p < 0.05 and p < 0.01) and control group (p < 0.01 and p < 0.01). The serum OPN level was significantly lower in the overweight/obese survivor than in the normal-weight survivor and control group (37.42 ng/mL [range, 27.32-62.07], 69.02 ng/mL [range, 40.29-88.21], and 85.7 ng/mL [range 67.7-102.3]; p < 0.01, p < 0.001, respectively). Serum OPN levels were inversely correlated with anthropometric measurements and HOMA-IR index in all the subjects. CONCLUSION Our results showed that obesity and IR are associated with decreased serum OPN levels in childhood survivors of ALL.
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Affiliation(s)
- Zeynep Canan Özdemir
- 1 Department of Pediatric Hematology/Oncology, Eskişehir Osmangazi University , Ekişehir, Turkey
| | - Yeter Düzenli Kar
- 1 Department of Pediatric Hematology/Oncology, Eskişehir Osmangazi University , Ekişehir, Turkey
| | - Meliha Demiral
- 2 Department of Pediatric Endocrinology, Eskişehir Osmangazi University , Ekişehir, Turkey
| | - Başar Sırmagül
- 3 Department of Pharmacology, Faculty of Medicine, Eskişehir Osmangazi University , Ekişehir, Turkey
| | - Özcan Bör
- 1 Department of Pediatric Hematology/Oncology, Eskişehir Osmangazi University , Ekişehir, Turkey
| | - Birgül Kırel
- 2 Department of Pediatric Endocrinology, Eskişehir Osmangazi University , Ekişehir, Turkey
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