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Duan F, Wu J, Chang J, Peng H, Liu Z, Liu P, Han X, Sun T, Shang D, Yang Y, Li Z, Li P, Liu Y, Zhu Y, Lv Y, Guo X, Zhao Y, An Y. Deciphering endocrine function of adipose tissue and its significant influences in obesity-related diseases caused by its dysfunction. Differentiation 2025; 141:100832. [PMID: 39709882 DOI: 10.1016/j.diff.2024.100832] [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: 10/29/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024]
Abstract
Current research has found that adipose tissue is not only involved in energy metabolism, but also a highly active endocrine organ that secretes various adipokines, including adiponectin, leptin, resistin and apelin, which are involved in the regulation of physiology and pathology of tissues and organs throughout the body. With the yearly increasing incidence, obesity has become a risk factor for a variety of pathological changes, including inflammation and metabolic syndrome in various system (endocrine, circulatory, locomotor and central nervous system). Thus these symptoms lead to multi-organ dysfunctions, including the heart, liver, kidneys, brain and joints. An in-depth summary of the roles of adipokines in the regulation of other tissues and organs can help to provide more effective therapeutic strategies for obesity-related diseases and explore potential therapeutic targets. Therefore, this review has retrospected the endocrine function of adipose tissue under obesity and the role of dysregulated adipokine secretion in related diseases and the underlying mechanisms, in order to provide a theoretical basis for targeting adipokine-mediated systemic dysregulation.
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Affiliation(s)
- Feiyi Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiaoyan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiayi Chang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Haoyuan Peng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zitao Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengfei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Dandan Shang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yutian Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zhihao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengkun Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yixuan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yonghao Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Yunzhi Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Xiumei Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Ying Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China.
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Barbosa P, Pinho A, Lázaro A, Paula D, Campos JC, Tralhão JG, Pereira MJ, Paiva A, Laranjeira P, Carvalho E. High percentage of immune Th1 and Tc1 cells infiltrating visceral adipose tissue in people with obesity. Obes Res Clin Pract 2024; 18:426-435. [PMID: 39765379 DOI: 10.1016/j.orcp.2024.12.006] [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: 05/14/2024] [Revised: 11/08/2024] [Accepted: 12/29/2024] [Indexed: 01/31/2025]
Abstract
Subcutaneous (SAT) and visceral (VAT) adipose tissue dysfunction during the obesity onset can lead to increased expression of inflammatory molecules, and consequently to immune cell infiltration. The aim was to deeply characterize the T cells, those infiltrating SAT and VAT, compared to peripheral blood (PB), in individuals undergoing bariatric surgery. Forty-two adult individuals were recruited, SAT and VAT samples were collected. T cell characterization was performed by flow cytometry. Results show that T cells infiltrating VAT from people with obesity display higher polarization towards Th1, Tc1 and T1-like CD4+CD8+ T cells, compared to SAT. These cells also display higher percentage of activated cells, and a higher percentage of PD-1-expressing cells. Furthermore, the percentage of Th1/17 and Tc1/17 cells was increased 7-18 months post-surgery. In summary, the phenotype of T cells and their expression of PD-1 within SAT and VAT appear different, especially compared to PB.
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Affiliation(s)
- Pedro Barbosa
- University of Coimbra, Institute for Interdisciplinary Research, Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Portugal; CNC-UC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão, Coimbra 3030-789, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal
| | - Aryane Pinho
- CNC-UC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal; Department of Life Science, University of Coimbra, Coimbra 3000-456, Portugal
| | - André Lázaro
- CNC-UC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal; General Surgery Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra 3000-061, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal
| | - Diogo Paula
- General Surgery Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra 3000-061, Portugal
| | - José C Campos
- General Surgery Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra 3000-061, Portugal
| | - José G Tralhão
- General Surgery Unit, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra 3000-061, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal; Institute of Biophysics, Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal
| | - Maria J Pereira
- Department of Medical Sciences, Clinical Diabetology and Metabolism, Uppsala University, Uppsala, Sweden
| | - Artur Paiva
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra 3000-061, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal; Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-076, Portugal; Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, Coimbra 3046-854, Portugal
| | - Paula Laranjeira
- CNC-UC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra 3000-061, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal; Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-076, Portugal.
| | - Eugenia Carvalho
- CNC-UC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão, Coimbra 3030-789, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal.
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Yadav R, Nigam A, Mishra R, Gupta S, Chaudhary AA, Khan SUD, almuqri EA, Ahmed ZH, Rustagi S, Singh DP, Kumar S. Novel Therapeutic Approach for Obesity: Seaweeds as an Alternative Medicine with the Latest Conventional Therapy. Med Sci (Basel) 2024; 12:55. [PMID: 39449411 PMCID: PMC11503287 DOI: 10.3390/medsci12040055] [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: 09/15/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/26/2024] Open
Abstract
The prevalence of overweight and obesity is increasing worldwide. Common comorbidities related to obesity, significantly polygenic disorders, cardiovascular disease, and heart conditions affect social and monetary systems. Over the past decade, research in drug discovery and development has opened new paths for alternative and conventional medicine. With a deeper comprehension of its underlying mechanisms, obesity is now recognized more as a chronic condition rather than merely a result of lifestyle choices. Nonetheless, addressing it solely through lifestyle changes is challenging due to the intricate nature of energy regulation dysfunction. The Federal Drug Administration (FDA) has approved six medications for the management of overweight and obesity. Seaweed are plants and algae that grow in oceans, rivers, and lakes. Studies have shown that seaweed has therapeutic potential in the management of body weight and obesity. Seaweed compounds such as carotenoids, xanthophyll, astaxanthin, fucoidans, and fucoxanthin have been demonstrated as potential bioactive components in the treatment of obesity. The abundance of natural seaweed bioactive compounds has been explored for their therapeutic potential for treating obesity worldwide. Keeping this view, this review covered the latest developments in the discovery of varied anti-obese seaweed and its bioactive components for the management of obesity.
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Affiliation(s)
- Rajesh Yadav
- Department of Dialysis Technology, Sharda School of Allied Health Science, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Department of Physiology, All India Institute of Medical Science, New Delhi 110029, India
| | - Ankita Nigam
- Department of Physiotherapy, Sharda School of Allied Health Science, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Richa Mishra
- Department of Computer Engineering, Parul Institute of Engineering and Technology (PIET), Parul University, Ta. Waghodia, Vadodara 391760, Gujarat, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura 281406, Uttar Pradesh, India
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
| | - Salah-Ud-Din Khan
- Department of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
| | - Eman Abdullah almuqri
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
| | - Zakir Hassain Ahmed
- Department of Mathematics and Statistics, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11632, Saudi Arabia
| | - Sarvesh Rustagi
- Department of Food Technology, School of Applied and Life Science, Uttaranchal University, Dehradun 248007, Uttarakhand, India
| | - Deependra Pratap Singh
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun 248002, Uttarakhand, India
| | - Sanjay Kumar
- Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
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Schuster-Little N, McCabe M, Nenninger K, Safavi-Sohi R, Whelan RJ, Hilliard TS. Generational Diet-Induced Obesity Remodels the Omental Adipose Proteome in Female Mice. Nutrients 2024; 16:3086. [PMID: 39339686 PMCID: PMC11435095 DOI: 10.3390/nu16183086] [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: 07/24/2024] [Revised: 08/16/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Obesity, a complex condition that involves genetic, environmental, and behavioral factors, is a non-infectious pandemic that affects over 650 million adults worldwide with a rapidly growing prevalence. A major contributor is the consumption of high-fat diets, an increasingly common feature of modern diets. Maternal obesity results in an increased risk of offspring developing obesity and related health problems; however, the impact of maternal diet on the adipose tissue composition of offspring has not been evaluated. Here, we designed a generational diet-induced obesity study in female C57BL/6 mice that included maternal cohorts and their female offspring fed either a control diet (10% fat) or a high-fat diet (45% fat) and examined the visceral adipose proteome. Solubilizing proteins from adipose tissue is challenging due to the need for high concentrations of detergents; however, the use of a detergent-compatible sample preparation strategy based on suspension trapping (S-Trap) enabled label-free quantitative bottom-up analysis of the adipose proteome. We identified differentially expressed proteins related to lipid metabolism, inflammatory disease, immune response, and cancer, providing valuable molecular-level insight into how maternal obesity impacts the health of offspring. Data are available via ProteomeXchange with the identifier PXD042092.
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Affiliation(s)
- Naviya Schuster-Little
- Department of Chemistry, University of Kansas, Lawrence, KS 66045, USA; (N.S.-L.); (R.J.W.)
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66047, USA
| | - Morgan McCabe
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (M.M.); (K.N.); (R.S.-S.)
| | - Kayla Nenninger
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (M.M.); (K.N.); (R.S.-S.)
| | - Reihaneh Safavi-Sohi
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (M.M.); (K.N.); (R.S.-S.)
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
- Department of Chemistry and Biochemistry, Seton Hall University, South Orange, NJ 07079, USA
| | - Rebecca J. Whelan
- Department of Chemistry, University of Kansas, Lawrence, KS 66045, USA; (N.S.-L.); (R.J.W.)
- Ralph N. Adams Institute for Bioanalytical Chemistry, University of Kansas, Lawrence, KS 66047, USA
| | - Tyvette S. Hilliard
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; (M.M.); (K.N.); (R.S.-S.)
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
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Yu GZ, Krentz NAJ, Bentley L, Zhao M, Paphiti K, Sun H, Honecker J, Nygård M, Dashti H, Bai Y, Reid M, Thaman S, Wabitsch M, Rajesh V, Yang J, Mattis KK, Abaitua F, Casero R, Hauner H, Knowles JW, Wu JY, Mandrup S, Claussnitzer M, Svensson KJ, Cox RD, Gloyn AL. Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.30.605923. [PMID: 39131393 PMCID: PMC11312556 DOI: 10.1101/2024.07.30.605923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1 +/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1 +/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.
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Affiliation(s)
- Grace Z. Yu
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK
| | - Nicole A. J. Krentz
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Liz Bentley
- MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK
- Mary Lyon Centre at MRC Harwell, Harwell Campus, Oxfordshire, UK
| | - Meng Zhao
- Department of Pathology, Stanford University, Stanford, CA, United States
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
| | - Keanu Paphiti
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK
| | - Han Sun
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Julius Honecker
- Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, School of Life Science, Technical University of Munich, 85354 Freising, Germany
| | - Marcus Nygård
- Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Hesam Dashti
- Broad Institute of MIT and Harvard, Novo Nordisk Foundation Center for Genomic Mechanisms of Disease & Type 2 Diabetes Systems Genomics Initiative, Cambridge, MA, USA
| | - Ying Bai
- MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK
- MRC Laboratory of Molecular Biology, Francis Crick Ave, Cambridge, CB2 0QH
| | - Madeleine Reid
- MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK
| | - Swaraj Thaman
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Martin Wabitsch
- Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany
- German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm, Germany
| | - Varsha Rajesh
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Jing Yang
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Katia K Mattis
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Fernando Abaitua
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Ramon Casero
- MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK
| | - Hans Hauner
- Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, School of Life Science, Technical University of Munich, 85354 Freising, Germany
- Institute for Nutritional Medicine, School of Medicine and Health, Technical University of Munich, Georg-Brauchle-Ring 62, Munich 80992, Germany
| | - Joshua W Knowles
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
- Division of Cardiovascular Medicine, Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California
| | - Joy Y Wu
- Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Susanne Mandrup
- Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Melina Claussnitzer
- Broad Institute of MIT and Harvard, Novo Nordisk Foundation Center for Genomic Mechanisms of Disease & Type 2 Diabetes Systems Genomics Initiative, Cambridge, MA, USA
- Center for Genomic Medicine and Endocrine Division, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Harvard University, Boston, Massachusetts, USA
| | - Katrin J Svensson
- Department of Pathology, Stanford University, Stanford, CA, United States
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
| | - Roger D. Cox
- MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK
| | - Anna L. Gloyn
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
- Lead Contact
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Iacobini C, Vitale M, Haxhi J, Menini S, Pugliese G. Impaired Remodeling of White Adipose Tissue in Obesity and Aging: From Defective Adipogenesis to Adipose Organ Dysfunction. Cells 2024; 13:763. [PMID: 38727299 PMCID: PMC11083890 DOI: 10.3390/cells13090763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.
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Choi C, Jeong YL, Park KM, Kim M, Kim S, Jo H, Lee S, Kim H, Choi G, Choi YH, Seong JK, Namgoong S, Chung Y, Jung YS, Granneman JG, Hyun YM, Kim JK, Lee YH. TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction. Nat Commun 2024; 15:2779. [PMID: 38555350 PMCID: PMC10981689 DOI: 10.1038/s41467-024-47108-8] [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: 10/17/2023] [Accepted: 03/20/2024] [Indexed: 04/02/2024] Open
Abstract
Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.
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Affiliation(s)
- Cheoljun Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yujin L Jeong
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea
| | - Koung-Min Park
- Department of Anatomy and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Minji Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sangseob Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Honghyun Jo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sumin Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Heeseong Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Garam Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yoon Ha Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center (KMPC), and Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Sik Namgoong
- Department of Plastic Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yeonseok Chung
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Young-Suk Jung
- Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
| | - James G Granneman
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.
| | - Young-Min Hyun
- Department of Anatomy and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Jong Kyoung Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
| | - Yun-Hee Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
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8
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Cho SY, Choi JS, Jung UJ. Effects of Ecklonia stolonifera Extract on Metabolic Dysregulation in High-Fat Diet-Induced Obese Mice. J Med Food 2024; 27:242-249. [PMID: 38354279 DOI: 10.1089/jmf.2023.k.0252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024] Open
Abstract
This study aimed to test the hypothesis that long-term and low-dose supplementation with an ethanol extract of Ecklonia stolonifera may confer protection against high-fat diet (HFD)-induced obesity in mice. Male C57BL/6J mice were divided into two groups, one of which was fed an HFD (40 kcal% fat) and the other an HFD+E. stolonifera (0.006%, w/w, ∼5 mg/kg body weight/day) for 16 weeks. E. stolonifera supplementation significantly reduced body weight from week 3 and until the end of the experiment. E. stolonifera-supplemented mice also exhibited lower fat mass (epididymal, perirenal, and mesenteric fat) and smaller adipocyte size than HFD control mice. The two groups displayed similar food intakes, but E. stolonifera markedly decreased lipogenesis and increased lipolysis and fatty acid oxidation in adipose tissue. Moreover, E. stolonifera significantly decreased plasma and hepatic lipid levels, hepatic lipid droplet accumulation, plasma aminotransferase levels, and liver weight by decreasing lipogenesis and increasing fatty acid oxidation. As E. stolonifera-supplemented mice showed improvements in hyperglycemia, insulin resistance, and inflammation, compared to control mice, it is possible that the beneficial effects of E. stolonifera on obesity might be associated with decreased inflammation and insulin resistance. Collectively, these results indicate that E. stolonifera could be used as a novel means of preventing and treating obesity and obesity-related metabolic disorders.
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Affiliation(s)
- Su Yeon Cho
- Department of Food Science and Nutrition, Pukyong National University, Busan, Korea
| | - Jae Sue Choi
- Department of Food Science and Nutrition, Pukyong National University, Busan, Korea
| | - Un Ju Jung
- Department of Food Science and Nutrition, Pukyong National University, Busan, Korea
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9
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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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10
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Ruhl T, Sessler TM, Keimes JM, Beier JP, Villwock S, Rose M, Dahl E. ITIH5 inhibits proliferation, adipogenic differentiation, and secretion of inflammatory cytokines of human adipose stem cells-A new key in treating obesity? FASEB J 2024; 38:e23352. [PMID: 38095340 DOI: 10.1096/fj.202301366r] [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: 07/06/2023] [Revised: 10/26/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023]
Abstract
Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is widely expressed in the human body, and it is detected to be particularly abundant in adipose tissue. ITIH5 expression is increased in people with obesity compared to lean persons and is decreased by diet-induced weight loss. This suggests that ITIH5 may be involved in the development of adiposity and clinical metabolic variables, although its exact function remains unknown. We measured the protein concentration of ITIH5 in adipose samples from patients undergoing abdominoplasty and tested for correlation with the subjects' BMI as well as inflammatory mediators. We stimulated human adipose stem cells (ASCs) with recombinant (r)ITIH5 protein and tested for an effect on proliferation, differentiation, and immunosuppressive properties when the cells were exposed to an artificial inflammatory environment. We found positive correlations between ITIH5 levels and the BMI (p < .001) as well as concentrations of inflammatory cytokines (TNF-α, IL-6, and MCP-1) in adipose tissue (p < .01). Application of the rITIH5 protein inhibited both proliferation (p < .001) and differentiation of ASCs. Especially, the development of mature adipocytes was reduced by over 50%. Moreover, rITIH5 decreased the release of IL-6 and MCP-1 when the cells were exposed to TNF-α and IL-1β (p < .001). Our data suggest that ITIH5 is an adipokine that is increasingly released during human adipose tissue development, acting as a regulator that inhibits proliferation and adipogenic differentiation of ASCs. ITIH5 thus presents itself as a positive regulator of adipose tissue homeostasis, possibly protecting against both hyperplasia and hypertrophy of adipose tissue and the associated chronic inflammation.
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Affiliation(s)
- Tim Ruhl
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Thomas M Sessler
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Jana M Keimes
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Justus P Beier
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Sophia Villwock
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Michael Rose
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Edgar Dahl
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
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11
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Umbayev B, Saliev T, Safarova (Yantsen) Y, Yermekova A, Olzhayev F, Bulanin D, Tsoy A, Askarova S. The Role of Cdc42 in the Insulin and Leptin Pathways Contributing to the Development of Age-Related Obesity. Nutrients 2023; 15:4964. [PMID: 38068822 PMCID: PMC10707920 DOI: 10.3390/nu15234964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/22/2023] [Accepted: 11/26/2023] [Indexed: 12/18/2023] Open
Abstract
Age-related obesity significantly increases the risk of chronic diseases such as type 2 diabetes, cardiovascular diseases, hypertension, and certain cancers. The insulin-leptin axis is crucial in understanding metabolic disturbances associated with age-related obesity. Rho GTPase Cdc42 is a member of the Rho family of GTPases that participates in many cellular processes including, but not limited to, regulation of actin cytoskeleton, vesicle trafficking, cell polarity, morphology, proliferation, motility, and migration. Cdc42 functions as an integral part of regulating insulin secretion and aging. Some novel roles for Cdc42 have also been recently identified in maintaining glucose metabolism, where Cdc42 is involved in controlling blood glucose levels in metabolically active tissues, including skeletal muscle, adipose tissue, pancreas, etc., which puts this protein in line with other critical regulators of glucose metabolism. Importantly, Cdc42 plays a vital role in cellular processes associated with the insulin and leptin signaling pathways, which are integral elements involved in obesity development if misregulated. Additionally, a change in Cdc42 activity may affect senescence, thus contributing to disorders associated with aging. This review explores the complex relationships among age-associated obesity, the insulin-leptin axis, and the Cdc42 signaling pathway. This article sheds light on the vast molecular web that supports metabolic dysregulation in aging people. In addition, it also discusses the potential therapeutic implications of the Cdc42 pathway to mitigate obesity since some new data suggest that inhibition of Cdc42 using antidiabetic drugs or antioxidants may promote weight loss in overweight or obese patients.
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Affiliation(s)
- Bauyrzhan Umbayev
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan; (Y.S.); (A.Y.); (F.O.); (A.T.); (S.A.)
| | - Timur Saliev
- S.D. Asfendiyarov Kazakh National Medical University, Almaty 050012, Kazakhstan;
| | - Yuliya Safarova (Yantsen)
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan; (Y.S.); (A.Y.); (F.O.); (A.T.); (S.A.)
| | - Aislu Yermekova
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan; (Y.S.); (A.Y.); (F.O.); (A.T.); (S.A.)
| | - Farkhad Olzhayev
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan; (Y.S.); (A.Y.); (F.O.); (A.T.); (S.A.)
| | - Denis Bulanin
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan;
| | - Andrey Tsoy
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan; (Y.S.); (A.Y.); (F.O.); (A.T.); (S.A.)
| | - Sholpan Askarova
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan; (Y.S.); (A.Y.); (F.O.); (A.T.); (S.A.)
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12
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Guo B, Shu H, Luo L, Liu X, Ma Y, Zhang J, Liu Z, Zhang Y, Fu L, Song T, Qiao Y, Zhang C. Lactate Conversion by Lactate Dehydrogenase B Is Involved in Beige Adipocyte Differentiation and Thermogenesis in Mice. Nutrients 2023; 15:4846. [PMID: 38004240 PMCID: PMC10674895 DOI: 10.3390/nu15224846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/06/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
Adipose tissue (AT) is the primary reservoir of lipid, the major thermogenesis organ during cold exposure, and an important site for lactate production. However, the utilization of lactate as a metabolic substrate by adipocytes, as well as its potential involvement in the regulation of adipocyte thermogenesis, remain unappreciated. In vitro experiments using primary stromal vascular fraction preadipocytes isolated from mouse inguinal white adipose tissue (iWAT) revealed that lactate dehydrogenase B (LDHB), the key glycolytic enzyme that catalyzes the conversion of lactate to pyruvate, is upregulated during adipocyte differentiation, downregulated upon chronic cold stimulation, and regained after prolonged cold exposure. In addition, the global knockout of Ldhb significantly reduced the masses of iWAT and epididymal WAT (eWAT) and impeded the utilization of iWAT during cold exposure. In addition, Ldhb loss of function impaired the mitochondrial function of iWAT under cold conditions. Together, these findings uncover the involvement of LDHB in adipocyte differentiation and thermogenesis.
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Affiliation(s)
- Bin Guo
- The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan 523018, China;
| | - Hui Shu
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
| | - Ling Luo
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
| | - Xiangpeng Liu
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
| | - Yue Ma
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
| | - Jie Zhang
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
| | - Zhiwei Liu
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
| | - Yong Zhang
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
| | - Lei Fu
- Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou 215123, China;
| | - Tongxing Song
- College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China;
| | - Yixue Qiao
- Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou 215123, China;
| | - Chi Zhang
- Cambridge-Suda Genomic Resource Center, Soochow University, Suzhou 215123, China; (H.S.); (L.L.); (X.L.); (Y.M.); (J.Z.); (Z.L.); (Y.Z.)
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13
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Santillana N, Astudillo-Guerrero C, D’Espessailles A, Cruz G. White Adipose Tissue Dysfunction: Pathophysiology and Emergent Measurements. Nutrients 2023; 15:nu15071722. [PMID: 37049561 PMCID: PMC10096946 DOI: 10.3390/nu15071722] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/27/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
White adipose tissue (AT) dysfunction plays an important role in the development of cardiometabolic alterations associated with obesity. AT dysfunction is characterized by the loss of the expansion capacity of the AT, an increment in adipocyte hypertrophy, and changes in the secretion profile of adipose cells, associated with accumulation of macrophages and inflammation. Since not all people with an excess of adiposity develop comorbidities, it is necessary to find simple tools that can evidence AT dysfunction and allow the detection of those people with the potential to develop metabolic alterations. This review focuses on the current pathophysiological mechanisms of white AT dysfunction and emerging measurements to assess its functionality.
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Affiliation(s)
- Natalia Santillana
- Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago 8380453, Chile
| | - Camila Astudillo-Guerrero
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
- Programa de Doctorado en Ciencias Mención Neurociencia, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Amanda D’Espessailles
- Instituto de Ciencias de la Salud, Universidad de O’Higgins, Rancagua 2820000, Chile
| | - Gonzalo Cruz
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
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14
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Liu Q, Li C, Deng B, Gao P, Wang L, Li Y, Shiri M, Alkaifi F, Zhao J, Stephens JM, Simintiras CA, Francis J, Sun J, Fu X. Tcf21 marks visceral adipose mesenchymal progenitors and functions as a rate-limiting factor during visceral adipose tissue development. Cell Rep 2023; 42:112166. [PMID: 36857185 PMCID: PMC10208561 DOI: 10.1016/j.celrep.2023.112166] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 01/01/2023] [Accepted: 02/09/2023] [Indexed: 03/02/2023] Open
Abstract
Distinct locations of different white adipose depots suggest anatomy-specific developmental regulation, a relatively understudied concept. Here, we report a population of Tcf21 lineage cells (Tcf21 LCs) present exclusively in visceral adipose tissue (VAT) that dynamically contributes to VAT development and expansion. During development, the Tcf21 lineage gives rise to adipocytes. In adult mice, Tcf21 LCs transform into a fibrotic or quiescent state. Multiomics analyses show consistent gene expression and chromatin accessibility changes in Tcf21 LC, based on which we constructed a gene-regulatory network governing Tcf21 LC activities. Furthermore, single-cell RNA sequencing (scRNA-seq) identifies the heterogeneity of Tcf21 LCs. Loss of Tcf21 promotes the adipogenesis and developmental progress of Tcf21 LCs, leading to improved metabolic health in the context of diet-induced obesity. Mechanistic studies show that the inhibitory effect of Tcf21 on adipogenesis is at least partially mediated via Dlk1 expression accentuation.
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Affiliation(s)
- Qianglin Liu
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA
| | - Chaoyang Li
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA
| | - Buhao Deng
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA; Department of Animal Sciences, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Peidong Gao
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA
| | - Leshan Wang
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA
| | - Yuxia Li
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA
| | - Mohammad Shiri
- Department of Computer Science, Old Dominion University, Norfolk, VA, USA
| | - Fozi Alkaifi
- Department of Computer Science, Old Dominion University, Norfolk, VA, USA
| | - Junxing Zhao
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA; Department of Animal Sciences, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Jacqueline M Stephens
- Pennington Biomedical Research Center, Baton Rouge, LA, USA; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA
| | | | - Joseph Francis
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | - Jiangwen Sun
- Department of Computer Science, Old Dominion University, Norfolk, VA, USA.
| | - Xing Fu
- School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA.
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15
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Kataoka H, Nitta K, Hoshino J. Visceral fat and attribute-based medicine in chronic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1097596. [PMID: 36843595 PMCID: PMC9947142 DOI: 10.3389/fendo.2023.1097596] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/13/2023] [Indexed: 02/11/2023] Open
Abstract
Visceral adipose tissue plays a central role in obesity and metabolic syndrome and is an independent risk factor for both cardiovascular and metabolic disorders. Increased visceral adipose tissue promotes adipokine dysregulation and insulin resistance, leading to several health issues, including systemic inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system. Moreover, an increase in adipose tissue directly and indirectly affects the kidneys by increasing renal sodium reabsorption, causing glomerular hyperfiltration and hypertrophy, which leads to increased proteinuria and kidney fibrosis/dysfunction. Although the interest in the adverse effects of obesity on renal diseases has grown exponentially in recent years, the relationship between obesity and renal prognosis remains controversial. This may be attributed to the long clinical course of obesity, numerous obesity-related metabolic complications, and patients' attributes. Multiple individual attributes influencing the pathophysiology of fat accumulation make it difficult to understand obesity. In such cases, it may be effective to elucidate the pathophysiology by conducting research tailored to individual attributes from the perspective of attribute-based medicine/personalized medicine. We consider the appropriate use of clinical indicators necessary, according to attributes such as chronic kidney disease stage, level of visceral adipose tissue accumulation, age, and sex. Selecting treatments and clinical indicators based on individual attributes will allow for advancements in the clinical management of patients with obesity and chronic kidney disease. In the clinical setting of obesity-related nephropathy, it is first necessary to accumulate attribute-based studies resulting from the accurate evaluation of visceral fat accumulation to establish evidence for promoting personalized medicine.
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16
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Zhu R, Chen S. Proteomic analysis reveals semaglutide impacts lipogenic protein expression in epididymal adipose tissue of obese mice. Front Endocrinol (Lausanne) 2023; 14:1095432. [PMID: 37025414 PMCID: PMC10070826 DOI: 10.3389/fendo.2023.1095432] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/28/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Obesity is a global health problem with few pharmacologic options. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that induces weight loss. Yet, the role of semaglutide in adipose tissue has not yet been examined. The following study investigated the mechanism of semaglutide on lipid metabolism by analyzing proteomics of epididymal white adipose tissue (eWAT) in obese mice. METHODS A total of 36 C57BL/6JC mice were randomly divided into a normal-chow diet group (NCD, n = 12), high-fat diet (HFD, n = 12), and HFD+semaglutide group (Sema, n = 12). Mice in the Sema group were intraperitoneally administered semaglutide, and the HFD group and the NCD group were intraperitoneally administered an equal volume of normal saline. Serum samples were collected to detect fasting blood glucose and blood lipids. The Intraperitoneal glucose tolerance test (IPGTT) was used to measure the blood glucose value at each time point and calculate the area under the glucose curve. Tandem Mass Tag (TMT) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to study the expression of eWAT, while cellular processes, biological processes, corresponding molecular functions, and related network molecular mechanisms were analyzed by bioinformatics. RESULTS Compared with the model group, the semaglutide-treated mice presented 640 differentially expressed proteins (DEPs), including 292 up-regulated and 348 down-regulated proteins. Bioinformatics analysis showed a reduction of CD36, FABP5, ACSL, ACOX3, PLIN2, ANGPTL4, LPL, MGLL, AQP7, and PDK4 involved in the lipid metabolism in the Sema group accompanied by a decrease in visceral fat accumulation, blood lipids, and improvement in glucose intolerance. CONCLUSION Semaglutide can effectively reduce visceral fat and blood lipids and improve glucose metabolism in obese mice. Semaglutide treatment might have beneficial effects on adipose tissues through the regulation of lipid uptake, lipid storage, and lipolysis in white adipose tissue.
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Affiliation(s)
- Ruiyi Zhu
- Department of Internal Medical, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Internal Medical, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Shuchun Chen
- Department of Internal Medical, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Internal Medical, Hebei General Hospital, Shijiazhuang, Hebei, China
- *Correspondence: Shuchun Chen,
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17
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Králová A, Kubátová H, Kauerová S, Janoušek L, Froněk J, Králová Lesná I, Poledne R. Cholesterol efflux and macrophage polarization in human adipose tissue. Physiol Res 2022. [DOI: 10.33549/physiolres.934926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The pro-inflammatory status of adipose tissue (AT) has been found to be related to reverse cholesterol transport (RCT) from peritoneal macrophages. However, this finding was made in experimental models using induced peritonitis and isolated peritoneal macrophages of animals. This experimental relationship is in agreement with RCT changes in man in two extreme situations, sepsis or cardiovascular complications.
Given the above, we sought to test RTC in relationship to macrophage polarization in the visceral AT (VAT) of living kidney donors (LKDs) and the effect of conditioned media obtained from their AT. The influence of ATCM on CE capacity was first assessed in an experiment where standard plasma was used as cholesterol acceptor from [14C] cholesterol labeled THP-1 cells. Conditioned media as a product of LKDs’ incubated AT showed no effect on CE. Likewise, we did not find any effect of individual plasma of LKDs on CE when individual plasma of LKDs were used as acceptors. On the other hand, we documented an effect of LKDs’ adipose cell size on CE. Our results indicate that the pro-inflammatory status of human AT is not likely induced by disrupted RCT but might be influenced by the metabolic status of LKDs’ adipose tissue.
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Affiliation(s)
| | | | | | | | | | | | - R Poledne
- Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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18
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Tremblay EJ, Tchernof A, Pelletier M, Chabot N, Joanisse DR, Mauriège P. Contribution of markers of adiposopathy and adipose cell size in predicting insulin resistance in women of varying age and adiposity. Adipocyte 2022; 11:175-189. [PMID: 35436409 PMCID: PMC9037496 DOI: 10.1080/21623945.2022.2059902] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/07/2022] [Accepted: 03/27/2022] [Indexed: 12/30/2022] Open
Abstract
Adipose tissue (AT) dysfunctions, such as adipocyte hypertrophy, macrophage infiltration and secretory adiposopathy (low plasma adiponectin/leptin, A/L, ratio), associate with metabolic disorders. However, no study has compared the relative contribution of these markers to cardiometabolic risk in women of varying age and adiposity. Body composition, regional AT distribution, lipid-lipoprotein profile, glucose homeostasis and plasma A and L levels were determined in 67 women (age: 40-62 years; BMI: 17-41 kg/m2). Expression of macrophage infiltration marker CD68 and adipocyte size were measured from subcutaneous abdominal (SCABD) and omental (OME) fat. AT dysfunction markers correlated with most lipid-lipoprotein levels. The A/L ratio was negatively associated with fasting insulinemia and HOMA-IR, while SCABD or OME adipocyte size and SCABD CD68 expression were positively related to these variables. Combination of tertiles of largest adipocyte size and lowest A/L ratio showed the highest HOMA-IR. Multiple regression analyses including these markers and TAG levels revealed that the A/L ratio was the only predictor of fasting insulinemia and HOMA-IR. The contribution of the A/L ratio was superseded by adipose cell size in the model where the latter replaced TAGs. Finally, leptinemia was a better predictor of IR than adipocyte size and the A/L ratio in our participants sample.
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Affiliation(s)
- Eve-Julie Tremblay
- Département de kinésiologie, Faculté de médecine, Université Laval, Québec, Canada
- Centre de recherche de l’institut Universitaire de cardiologie et pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Canada
| | - André Tchernof
- Centre de recherche de l’institut Universitaire de cardiologie et pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Canada
- École de Nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, Québec, Canada
| | - Mélissa Pelletier
- Centre de recherche de l’institut Universitaire de cardiologie et pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Canada
| | - Nicolas Chabot
- Département de kinésiologie, Faculté de médecine, Université Laval, Québec, Canada
- Centre de recherche de l’institut Universitaire de cardiologie et pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Canada
| | - Denis R. Joanisse
- Département de kinésiologie, Faculté de médecine, Université Laval, Québec, Canada
- Centre de recherche de l’institut Universitaire de cardiologie et pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Canada
| | - Pascale Mauriège
- Département de kinésiologie, Faculté de médecine, Université Laval, Québec, Canada
- Centre de recherche de l’institut Universitaire de cardiologie et pneumologie de Québec (CRIUCPQ), Université Laval, Québec, Canada
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KRÁLOVÁ A, BARTUŠKOVÁ H, KAUEROVÁ S, JANOUŠEK L, FRONĚK J, KRÁLOVÁ LESNÁ I, POLEDNE R. Cholesterol efflux and macrophage polarization in human adipose tissue. Physiol Res 2022; 71:859-868. [PMID: 36426890 PMCID: PMC9814980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The pro-inflammatory status of adipose tissue (AT) has been found to be related to reverse cholesterol transport (RCT) from peritoneal macrophages. However, this finding was made in experimental models using induced peritonitis and isolated peritoneal macrophages of animals. This experimental relationship is in agreement with RCT changes in man in two extreme situations, sepsis or cardiovascular complications. Given the above, we sought to test RTC in relationship to macrophage polarization in the visceral AT (VAT) of living kidney donors (LKDs) and the effect of conditioned media obtained from their AT. The influence of ATCM on CE capacity was first assessed in an experiment where standard plasma was used as cholesterol acceptor from [14C] cholesterol labeled THP-1. Conditioned media as a product of LKDs' incubated AT showed no effect on CE. Likewise, we did not find any effect of individual plasma of LKDs on CE when individual plasma of LKDs were used as acceptors. On the other hand, we documented an effect of LKDs' adipose cell size on CE. Our results indicate that the pro-inflammatory status of human AT is not likely induced by disrupted RCT but might be influenced by the metabolic status of LKDs' adipose tissue.
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Affiliation(s)
- Anna KRÁLOVÁ
- Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic,Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Hana BARTUŠKOVÁ
- Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic,Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Soňa KAUEROVÁ
- Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Libor JANOUŠEK
- Transplantation Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jiří FRONĚK
- Transplantation Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ivana KRÁLOVÁ LESNÁ
- Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic,First Faculty of Medicine, Charles University, Military University Hospital, Prague, Czech Republic
| | - Rudolf POLEDNE
- Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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20
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Adipocyte size, adipose tissue fibrosis, macrophage infiltration and disease risk are different in younger and older individuals with childhood versus adulthood onset obesity. Int J Obes (Lond) 2022; 46:1859-1866. [PMID: 35927468 DOI: 10.1038/s41366-022-01192-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND The timing of obesity onset and age have been shown to affect the risk of obesity-related comorbidities, although the impact of each of these factors on markers of adipose tissue function remains unclear. OBJECTIVE The aim of this study was to determine whether differences in regional adipose tissue characteristics vary with age and age of obesity onset, and whether these differences are associated with the markers of cardiometabolic health. METHODS Adipose tissue samples were obtained from 80 female bariatric surgery candidates who were classified by age of obesity onset and age into 4 groups: (1) younger adults (<40 y) with childhood-onset obesity (<18 y) (Child-Young); (2) younger adults with adulthood-onset obesity (>18 y) (Adult-Young); (3) older adults (>55 y) with childhood-onset obesity (Child-Old); and (4) older adults with adulthood-onset obesity (Adult-Old). Adipocyte diameter, adipose tissue fibrosis, and macrophage infiltration were determined in subcutaneous (SAT) and visceral adipose tissue (VAT). Clinical parameters were obtained from participants' medical records. RESULTS Visceral adipocyte size in the Child-Young group was the smallest of all the groups. Age affected visceral infiltration of M1-like cells with greater percent of M1-like cells in the Adult-Old and Child-Old groups. Though not significant, a stepwise increase in M2-like macrophages in VAT was observed with Adult-Young having the smallest followed by Adult-Old, Child-Young, and Child-Old having the greatest percent of M2-like macrophages. Pericellular fibrosis accumulation in SAT and VAT varied with both age and onset, particularly in the Child-Old group, which had the lowest fibrosis levels. Markers of cardiometabolic health (fasting glucose, glycated hemoglobin, total, HDL- and LDL-cholesterol and triglyceride concentrations) were positively and well-associated with adipose tissue characteristics of the Child-Old group but not of the Adult-Young group. CONCLUSION Older adults with childhood-onset obesity, who had the greatest duration of obesity exposure, were particularly vulnerable to the cardiometabolic effects associated with perturbations in adipose tissue characteristics. These results suggest that age and age of obesity onset may have independent and cumulative effects on obesity pathology.
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21
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Honecker J, Ruschke S, Seeliger C, Laber S, Strobel S, Pröll P, Nellaker C, Lindgren CM, Kulozik U, Ecker J, Karampinos DC, Claussnitzer M, Hauner H. Transcriptome and fatty-acid signatures of adipocyte hypertrophy and its non-invasive MR-based characterization in human adipose tissue. EBioMedicine 2022; 79:104020. [PMID: 35490555 PMCID: PMC9062743 DOI: 10.1016/j.ebiom.2022.104020] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/07/2022] [Accepted: 04/07/2022] [Indexed: 12/13/2022] Open
Abstract
Background The adipocyte-hypertrophy associated remodeling of fat cell function is considered causal for the development of metabolic disorders. A better understanding of transcriptome and fatty acid (FA) related alterations with adipocyte hypertrophy combined with less-invasive strategies for the detection of the latter can help to increase the prognostic and diagnostic value of adipocyte size and FA composition as markers for metabolic disease. Methods To clarify adipocyte-hypertrophy associated transcriptomic alterations, fat cell size was related to RNA-Seq data from white adipose tissue and size-separated adipocytes. The relationship between adipocyte size and adipose tissue FA composition as measured by GC-MS was investigated. MR spectroscopy (MRS) methods for clinical scanning were developed to characterize adipocyte size and FA composition in a fast and non-invasive manner. Findings With enlarged adipocyte size, substantial transcriptomic alterations of genes involved in mitochondrial function and FA metabolism were observed. Investigations of these two mechanisms revealed a reciprocal relationship between adipocyte size and estimated thermogenic adipocyte content as well as depot-specific correlations of adipocyte size and FA composition. MRS on a clinical scanner was suitable for the in-parallel assessment of adipose morphology and FA composition. Interpretation The current study provides a comprehensive overview of the adipocyte-hypertrophy associated transcriptomic and FA landscape in both subcutaneous and visceral adipose tissue. MRS represents a promising technique to translate the observed mechanistic, structural and functional changes in WAT with adipocyte hypertrophy into a clinical context for an improved phenotyping of WAT in the context of metabolic diseases. Funding Competence network for obesity (FKZ 42201GI1128), ERC (No 677661, ProFatMRI; No 875488, FatVirtualBiopsy), Else Kröner-Fresenius-Foundation.
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22
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The Shades of Grey in Adipose Tissue Reprogramming. Biosci Rep 2022; 42:230844. [PMID: 35211733 PMCID: PMC8905306 DOI: 10.1042/bsr20212358] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 11/22/2022] Open
Abstract
The adipose tissue (AT) has a major role in contributing to obesity-related pathologies through regulating systemic immunometabolism. The pathogenicity of the AT is underpinned by its remarkable plasticity to be reprogrammed during obesity, in the perspectives of tissue morphology, extracellular matrix (ECM) composition, angiogenesis, immunometabolic homoeostasis and circadian rhythmicity. Dysregulation in these features escalates the pathogenesis conferred by this endometabolic organ. Intriguingly, the potential to be reprogrammed appears to be an Achilles’ heel of the obese AT that can be targeted for the management of obesity and its associated comorbidities. Here, we provide an overview of the reprogramming processes of white AT (WAT), with a focus on their dynamics and pleiotropic actions over local and systemic homoeostases, followed by a discussion of potential strategies favouring therapeutic reprogramming. The potential involvement of AT remodelling in the pathogenesis of COVID-19 is also discussed.
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Ye RZ, Richard G, Gévry N, Tchernof A, Carpentier AC. Fat Cell Size: Measurement Methods, Pathophysiological Origins, and Relationships With Metabolic Dysregulations. Endocr Rev 2022; 43:35-60. [PMID: 34100954 PMCID: PMC8755996 DOI: 10.1210/endrev/bnab018] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Indexed: 11/19/2022]
Abstract
The obesity pandemic increasingly causes morbidity and mortality from type 2 diabetes, cardiovascular diseases and many other chronic diseases. Fat cell size (FCS) predicts numerous obesity-related complications such as lipid dysmetabolism, ectopic fat accumulation, insulin resistance, and cardiovascular disorders. Nevertheless, the scarcity of systematic literature reviews on this subject is compounded by the use of different methods by which FCS measurements are determined and reported. In this paper, we provide a systematic review of the current literature on the relationship between adipocyte hypertrophy and obesity-related glucose and lipid dysmetabolism, ectopic fat accumulation, and cardiovascular disorders. We also review the numerous mechanistic origins of adipocyte hypertrophy and its relationship with metabolic dysregulation, including changes in adipogenesis, cell senescence, collagen deposition, systemic inflammation, adipokine secretion, and energy balance. To quantify the effect of different FCS measurement methods, we performed statistical analyses across published data while controlling for body mass index, age, and sex.
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Affiliation(s)
- Run Zhou Ye
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Gabriel Richard
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Nicolas Gévry
- Department of Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - André Tchernof
- Québec Heart and Lung Research Institute, Laval University, Québec, Québec, Canada
| | - André C Carpentier
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
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24
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Pincu Y, Yoel U, Haim Y, Makarenkov N, Maixner N, Shaco-Levy R, Bashan N, Dicker D, Rudich A. Assessing Obesity-Related Adipose Tissue Disease (OrAD) to Improve Precision Medicine for Patients Living With Obesity. Front Endocrinol (Lausanne) 2022; 13:860799. [PMID: 35574032 PMCID: PMC9098964 DOI: 10.3389/fendo.2022.860799] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 03/15/2022] [Indexed: 12/21/2022] Open
Abstract
Obesity is a heterogenous condition that affects the life and health of patients to different degrees and in different ways. Yet, most approaches to treat obesity are not currently prescribed, at least in a systematic manner, based on individual obesity sub-phenotypes or specifically-predicted health risks. Adipose tissue is one of the most evidently affected tissues in obesity. The degree of adipose tissue changes - "adiposopathy", or as we propose to relate to herein as Obesity-related Adipose tissue Disease (OrAD), correspond, at least cross-sectionally, to the extent of obesity-related complications inflicted on an individual patient. This potentially provides an opportunity to better personalize anti-obesity management by utilizing the information that can be retrieved by assessing OrAD. This review article will summarize current knowledge on histopathological OrAD features which, beyond cross-sectional analyses, had been shown to predict future obesity-related endpoints and/or the response to specific anti-obesity interventions. In particular, the review explores adipocyte cell size, adipose tissue inflammation, and fibrosis. Rather than highly-specialized methods, we emphasize standard pathology laboratory approaches to assess OrAD, which are readily-available in most clinical settings. We then discuss how OrAD assessment can be streamlined in the obesity/weight-management clinic. We propose that current studies provide sufficient evidence to inspire concerted efforts to better explore the possibility of predicting obesity related clinical endpoints and response to interventions by histological OrAD assessment, in the quest to improve precision medicine in obesity.
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Affiliation(s)
- Yair Pincu
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- Department of Health and Exercise Science, University of Oklahoma, Norman, OK, United States
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Uri Yoel
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- The Endocrinology Service, Soroka University Medical Center, Beer-Sheva, Israel
| | - Yulia Haim
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Nataly Makarenkov
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Nitzan Maixner
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Ruthy Shaco-Levy
- Institute of Pathology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Nava Bashan
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Dror Dicker
- Department of Internal Medicine D, Hasharon Hospital, Rabin Medical Center, Petah Tikva, Israel
- Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel
- *Correspondence: Assaf Rudich, ; Dror Dicker,
| | - Assaf Rudich
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
- The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
- *Correspondence: Assaf Rudich, ; Dror Dicker,
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Recombinant human GLP-1 beinaglutide regulates lipid metabolism of adipose tissues in diet-induced obese mice. iScience 2021; 24:103382. [PMID: 34841227 PMCID: PMC8605346 DOI: 10.1016/j.isci.2021.103382] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/19/2021] [Accepted: 10/27/2021] [Indexed: 01/18/2023] Open
Abstract
GLP-1 analogs are a class of glucose-lowering agents with multiple benefits in diabetes, but its role in adipose tissues remains to be elucidated. The aim of this study was to determine the action of recombinant human GLP-1 (rhGLP-1) Beinaglutide (BN) in the insulin sensitivity and lipid metabolism of adipose tissues. We have shown that, after BN injection, obese mice displayed lower body weight, fat mass, and plasma lipid levels. In addition, BN promoted the insulin sensitivity in the white adipose tissues. Furthermore, we have found that the BN treatment caused significant changes in content and composition of different lipid classes, including glycerolipids, glycerophospholipids, and sphingolipids, as well as expression of genes in lipid metabolic pathways in the adipose tissues. Taken together, our data demonstrate that BN could resist HFD-induced obesity by targeting the composition of major lipid classes and the expression of genes in lipid metabolism of adipose tissues.
Recombinant human GLP-1 Beinaglutide (BN) reduces high-fat-diet-induced obesity BN increases insulin sensitivity of adipocytes in vivo and in vitro BN alters lipidomic and transcriptomic profiles in adipose tissues of obese mice BN promotes thermogenic gene expression in adipose tissues
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Liu F, He J, Liu B, Zhang P, Wang H, Sun X, Chu X, Guan W, Feng W, Bi Y, Zhu D. Association of Omental Adipocyte Hypertrophy and Fibrosis with Human Obesity and Type 2 Diabetes. Obesity (Silver Spring) 2021; 29:976-984. [PMID: 33943025 DOI: 10.1002/oby.23155] [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: 09/03/2020] [Revised: 02/04/2021] [Accepted: 02/07/2021] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Morphological alterations including adipocyte hypertrophy and fibrosis deposition are important surrogate markers of visceral adipose tissue function, but the relationships between these morphological changes and type 2 diabetes mellitus (T2DM) and impaired insulin sensitivity are poorly defined. METHODS Omental adipose tissue was obtained from 66 individuals with obesity but without T2DM (OB group), 93 individuals with both obesity and T2DM (T2DM group), and 15 individuals with normal BMI and normal glucose tolerance (NGT group). Adipocyte diameter and volume were measured through pathological section analysis. Pericellular and perilobular fibrosis was determined through picrosirius red staining and immunochemistry, while fibrosis-related genes were tested through gene expression and hydroxyproline content. RESULTS Compared with the NGT and OB groups, individuals from the T2DM group displayed increased adipocyte diameter and volume levels. Increased adipocyte size (diameter and volume) was positively associated with hyperglycemia and insulin resistance and inversely correlated with insulin sensitivity (using the Matsuda whole-body insulin sensitivity index assessment of insulin sensitivity) and β-cell function (disposition index 30 and disposition index 120). The fibrosis levels of the OB group were the highest out of the three groups, whereas the fibrosis levels of T2DM individuals were lower than the OB group but higher than the NGT group. Although fibrosis was negatively correlated with T2DM, fibrosis deposition was not remarkably associated with impaired systemic insulin sensitivity and glucose metabolism. CONCLUSIONS Compared with fibrosis deposition, adipocyte hypertrophy is more closely associated with T2DM and impaired systemic insulin sensitivity.
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Affiliation(s)
- Fangcen Liu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
- Department of Pathology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jielei He
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Boxun Liu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Pengzi Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Hongdong Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xitai Sun
- Department of General Surgery, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xuehui Chu
- Department of General Surgery, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenxian Guan
- Department of General Surgery, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenhuan Feng
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
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Morigny P, Boucher J, Arner P, Langin D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat Rev Endocrinol 2021; 17:276-295. [PMID: 33627836 DOI: 10.1038/s41574-021-00471-8] [Citation(s) in RCA: 290] [Impact Index Per Article: 72.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/15/2021] [Indexed: 12/14/2022]
Abstract
In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.
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Affiliation(s)
- Pauline Morigny
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Toulouse, France
- University of Toulouse, Paul Sabatier University, I2MC, UMR1297, Toulouse, France
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jeremie Boucher
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- The Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Peter Arner
- Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
| | - Dominique Langin
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Toulouse, France.
- University of Toulouse, Paul Sabatier University, I2MC, UMR1297, 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, Toulouse, France.
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28
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de Medeiros SF, Rodgers RJ, Norman RJ. Adipocyte and steroidogenic cell cross-talk in polycystic ovary syndrome. Hum Reprod Update 2021; 27:771-796. [PMID: 33764457 DOI: 10.1093/humupd/dmab004] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/08/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Metabolic and endocrine alterations in women with polycystic ovary syndrome (PCOS) affect adipose tissue mass and distribution. PCOS is characterised by hyperandrogenism, obesity and adipocyte dysfunction. Hyperandrogenism in PCOS drives dysfunctional adipocyte secretion of potentially harmful adipocytokines. Glucocorticoids and sex-steroids modulate adipocyte development and function. For their part, adipocyte products interact with adrenal and ovarian steroidogenic cells. Currently, the relationship between adipocyte and steroidogenic cells is not clear, and for these reasons, it is important to elucidate the interrelationship between these cells in women with and without PCOS. OBJECTIVE AND RATIONALE This comprehensive review aims to assess current knowledge regarding the interrelationship between adipocytes and adrenal and ovarian steroidogenic cells in animal models and humans with or without PCOS. SEARCH METHODS We searched for articles published in English and Portuguese in PubMed. Keywords were as follows: polycystic ovary syndrome, steroidogenesis, adrenal glands, theca cells, granulosa cells, adipocytes, adipocytokines, obesity, enzyme activation, and cytochrome P450 enzymes. We expanded the search into the references from the retrieved articles. OUTCOMES Glucocorticoids and sex-steroids modulate adipocyte differentiation and function. Dysfunctional adipocyte products play important roles in the metabolic and endocrine pathways in animals and women with PCOS. Most adipokines participate in the regulation of the hypothalamic-pituitary-adrenal and ovarian axes. In animal models of PCOS, hyperinsulinemia and poor fertility are common; various adipokines modulate ovarian steroidogenesis, depending on the species. Women with PCOS secrete unbalanced levels of adipocyte products, characterised by higher levels of leptin and lower levels of adiponectin. Leptin expression positively correlates with body mass index, waist/hip ratio and levels of total cholesterol, triglyceride, luteinising hormone, oestradiol and androgens. Leptin inhibits the production of oestradiol and, in granulosa cells, may modulate 17-hydroxylase and aromatase enzyme activities. Adiponectin levels negatively correlate with fat mass, body mass index, waist-hip ratio, glucose, insulin and triglycerides, and decrease androgen production by altering expression of luteinising hormone receptor, steroidogenic acute regulatory protein, cholesterol-side-chain cleavage enzyme and 17-hydroxylase. Resistin expression positively correlates with body mass index and testosterone, and promotes the expression of 17-hydroxylase enzyme in theca cells. The potential benefits of adipokines in the treatment of women with PCOS require more investigation. WIDER IMPLICATIONS The current data regarding the relationship between adipocyte products and steroidogenic cells are conflicting in animals and humans. Polycystic ovary syndrome is an excellent model to investigate the interrelationship among adipocyte and steroidogenic cells. Women with PCOS manifest some pathological conditions associated with hyperandrogenism and adipocyte products. In animals, cross-talk between cells may vary according to species, and the current review suggests opportunities to test new medications to prevent or even reverse several harmful sequelae of PCOS in humans. Further studies are required to investigate the possible therapeutic application of adipokines in women with obese and non-obese PCOS. Meanwhile, when appropriate, metformin use alone, or associated with flutamide, may be considered for therapeutic purposes.
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Affiliation(s)
- Sebastião Freitas de Medeiros
- Department of Gynecology and Obstetrics, Medical School, Federal University of Mato Grosso; and Tropical Institute of Reproductive Medicine,Cuiabá, MT, Brazil
| | - Raymond Joseph Rodgers
- Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia, Australia
| | - Robert John Norman
- Robinson Research Institute Adelaide Medical School, Adelaide, South Australia, Australia
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Teklu M, Zhou W, Kapoor P, Patel N, Dey AK, Sorokin AV, Manyak GA, Teague HL, Erb-Alvarez JA, Sajja A, Abdelrahman KM, Reddy AS, Uceda DE, Lateef SS, Shanbhag SM, Scott C, Prakash N, Svirydava M, Parel P, Rodante JA, Keel A, Siegel EL, Chen MY, Bluemke DA, Playford MP, Gelfand JM, Mehta NN. Metabolic syndrome and its factors are associated with noncalcified coronary burden in psoriasis: An observational cohort study. J Am Acad Dermatol 2021; 84:1329-1338. [PMID: 33383084 DOI: 10.1016/j.jaad.2020.12.044] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Psoriasis is associated with a heightened risk of cardiovascular disease and higher prevalence of metabolic syndrome. OBJECTIVE Investigate the effect of metabolic syndrome and its factors on early coronary artery disease assessed as noncalcified coronary burden by coronary computed tomography angiography in psoriasis. METHODS This cross-sectional study consisted of 260 participants with psoriasis and coronary computed tomography angiography characterization. Metabolic syndrome was defined according to the harmonized International Diabetes Federation criteria. RESULTS Of the 260 participants, 80 had metabolic syndrome (31%). The metabolic syndrome group had a higher burden of cardiometabolic disease, systemic inflammation, noncalcified coronary burden, and high-risk coronary plaque. After adjusting for Framingham risk score, lipid-lowering therapy, and biologic use, metabolic syndrome (β = .31; P < .001) and its individual factors of waist circumference (β = .33; P < .001), triglyceride levels (β = .17; P = .005), blood pressure (β = .18; P = .005), and fasting glucose (β = .17; P = .009) were significantly associated with noncalcified coronary burden. After adjusting for all other metabolic syndrome factors, blood pressure and waist circumference remained significantly associated with noncalcified coronary burden. LIMITATIONS Observational nature with limited ability to control for confounders. CONCLUSIONS In psoriasis, individuals with metabolic syndrome had more cardiovascular disease risk factors, systemic inflammation, and noncalcified coronary burden. Efforts to increase metabolic syndrome awareness in psoriasis should be undertaken to reduce the heightened cardiovascular disease risk.
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Affiliation(s)
- Meron Teklu
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Wunan Zhou
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Promita Kapoor
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Nidhi Patel
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Amit K Dey
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Alexander V Sorokin
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Grigory A Manyak
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Heather L Teague
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Julie A Erb-Alvarez
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Aparna Sajja
- Department of Internal Medicine, Johns Hopkins University Medical Center, Baltimore, Maryland
| | - Khaled M Abdelrahman
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Aarthi S Reddy
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Domingo E Uceda
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Sundus S Lateef
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Sujata M Shanbhag
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Colin Scott
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Nina Prakash
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Maryia Svirydava
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Philip Parel
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Justin A Rodante
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Andrew Keel
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Evan L Siegel
- Department of Rheumatology, Arthritis and Rheumatism Associates, Rockville, Maryland
| | - Marcus Y Chen
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - David A Bluemke
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Martin P Playford
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Joel M Gelfand
- Department of Dermatology, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Nehal N Mehta
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
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Alvarez-Silvares E, Fernández-Cruz T, Domínguez-Vigo P, Rubio-Cid P, Seoane-Pillado T, Martínez-Carballo E. Association between placenta concentrations polybrominated and polychlorinated biphenyls and gestational diabetes mellitus: a case-control study in northwestern Spain. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:10292-10301. [PMID: 33462692 DOI: 10.1007/s11356-021-12377-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 01/04/2021] [Indexed: 06/12/2023]
Abstract
Exposure to persistent organic pollutants begins in uterine life. The study was conducted to evaluate associations between gestational diabetes mellitus and the presence of persistent organic pollutants in placenta samples. They were derived from a birth cohort study in Ourense (NW Spain). Selective pressurized liquid extraction methodologies were used to determine targeted persistent organic pollutants in placenta samples. Cleanup of extracts was performed by solid-phase extraction using EZ-POP cartridges and detection by gas chromatography coupled to tandem mass spectrometry. Statistical calculations were performed by comparing the values obtained in the case and control groups. Statistical significance was considered as p < 0.050. Results: The concentrations of several congeners of polybrominated diphenyl ethers (PBDE) and polychlorinated biphenyls (PCB) presented lower levels in the placentas of expectant mothers with gestational diabetes mellitus when comparing them to the control cohort. This difference was statistically significant. It was revealed that this association was independent of obesity, age, parity, amenorrhoea at birth, or a family history of diabetes mellitus. To the best of our knowledge, this paper reported an inverse relationship between PBDE and PCB levels in placenta and gestational diabetes mellitus for the first time. We believe this may open a door to future studies in this field.
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Affiliation(s)
- Esther Alvarez-Silvares
- Obstetrics and Gynaecology Department, Complexo Hospitalario Universitario de Ourense, C/ Ramón Puga 54, 32005, Ourense, Spain.
| | - Tania Fernández-Cruz
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Agri-Food Research and Transfer Cluster (CITACA), Campus da Auga, Faculty of Sciences of the University of Vigo, 32004, Ourense, Spain
| | - Paula Domínguez-Vigo
- Obstetrics and Gynaecology Department, Complexo Hospitalario Universitario de Ourense, C/ Ramón Puga 54, 32005, Ourense, Spain
| | - Paula Rubio-Cid
- Obstetrics and Gynaecology Department, Complexo Hospitalario Universitario de Ourense, C/ Ramón Puga 54, 32005, Ourense, Spain
| | | | - Elena Martínez-Carballo
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Agri-Food Research and Transfer Cluster (CITACA), Campus da Auga, Faculty of Sciences of the University of Vigo, 32004, Ourense, Spain
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A distribution-centered approach for analyzing human adipocyte size estimates and their association with obesity-related traits and mitochondrial function. Int J Obes (Lond) 2021; 45:2108-2117. [PMID: 34172828 PMCID: PMC8380540 DOI: 10.1038/s41366-021-00883-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/10/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Cell diameter, area, and volume are established quantitative measures of adipocyte size. However, these different adipocyte sizing parameters have not yet been directly compared regarding their distributions. Therefore, the study aimed to investigate how these adipocyte size measures differ in their distribution and assessed their correlation with anthropometry and laboratory chemistry. In addition, we were interested to investigate the relationship between fat cell size and adipocyte mitochondrial respiratory chain capacity. METHODS Subcutaneous and visceral histology-based adipocyte size estimates from 188 individuals were analyzed by applying a panel of parameters to describe the underlying cell population. Histology-based adipocyte diameter distributions were compared with adipocyte diameter distributions from collagenase digestion. Associations of mean adipocyte size with body mass index (BMI), glucose, HbA1C, blood lipids as well as mature adipocyte mitochondrial respiration were investigated. RESULTS All adipocyte area estimates derived from adipose tissue histology were not normally distributed, but rather characterized by positive skewness. The shape of the size distribution depends on the adipocyte sizing parameter and on the method used to determine adipocyte size. Despite different distribution shapes histology-derived adipocyte area, diameter, volume, and surface area consistently showed positive correlations with BMI. Furthermore, associations between adipocyte sizing parameters and glucose, HbA1C, or HDL specifically in the visceral adipose depot were revealed. Increasing subcutaneous adipocyte diameter was negatively correlated with adipocyte mitochondrial respiration. CONCLUSIONS Despite different underlying size distributions, the correlation with obesity-related traits was consistent across adipocyte sizing parameters. Decreased mitochondrial respiratory capacity with increasing subcutaneous adipocyte diameter could display a novel link between adipocyte hypertrophy and adipose tissue function.
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Goossens GH, Jocken JWE, Blaak EE. Sexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver. Nat Rev Endocrinol 2021; 17:47-66. [PMID: 33173188 DOI: 10.1038/s41574-020-00431-8] [Citation(s) in RCA: 199] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2020] [Indexed: 12/11/2022]
Abstract
Obesity is associated with many adverse health effects, such as an increased cardiometabolic risk. Despite higher adiposity for a given BMI, premenopausal women are at lower risk of cardiometabolic disease than men of the same age. This cardiometabolic advantage in women seems to disappear after the menopause or when type 2 diabetes mellitus develops. Sexual dimorphism in substrate supply and utilization, deposition of excess lipids and mobilization of stored lipids in various key metabolic organs (such as adipose tissue, skeletal muscle and the liver) are associated with differences in tissue-specific insulin sensitivity and cardiometabolic risk profiles between men and women. Moreover, lifestyle-related factors and epigenetic and genetic mechanisms seem to affect metabolic complications and disease risk in a sex-specific manner. This Review provides insight into sexual dimorphism in adipose tissue distribution, adipose tissue, skeletal muscle and liver substrate metabolism and tissue-specific insulin sensitivity in humans, as well as the underlying mechanisms, and addresses the effect of these sex differences on cardiometabolic health. Additionally, this Review highlights the implications of sexual dimorphism in the pathophysiology of obesity-related cardiometabolic risk for the development of sex-specific prevention and treatment strategies.
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Affiliation(s)
- Gijs H Goossens
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, Netherlands.
| | - Johan W E Jocken
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Ellen E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, Netherlands.
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Lu X, Wang Q, Liang H, Xu L, Sha L, Wu Y, Ma L, Yang P, Lei H. Contribution of Different Phenotypes of Obesity to Metabolic Abnormalities from a Cross-Sectional Study in the Northwest China. Diabetes Metab Syndr Obes 2021; 14:3111-3121. [PMID: 34262315 PMCID: PMC8273743 DOI: 10.2147/dmso.s314935] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/16/2021] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND This study has been conducted to explore the correlation between phenotypes of obesity and metabolic comorbidities. METHODS This cross-sectional study recruited 14,724 adults aged ≥18 years with a randomized stratified sampling strategy. Obesity was classified into four types according to body mass index (BMI) and waist-to-height ratio (WHtR): normal weight with central obesity (NWCO) and without (NW) CO, and obese or overweight with (OBCO) and without (OB) central obesity. Uric acid (UA), fasting blood glucose (FBG), and lipid profile were measured. RESULTS The prevalence of hyperuricemia in the 4 groups (NW, NWCO, OB and OBCO) was 3.7%, 5.6%, 8.7% and 12.4%, whilst the prevalence of hypertriglyceridemia was 13.4%, 27.4%, 30.3% and 43.7%, separately. The prevalence of hypo-high-density lipoprotein cholesterolemia (hypo-HDL emia) was 20.1%, 21.4%, 30.8% and 27.9%, while the prevalence of hyper-low-density lipoprotein cholesterolemia (hyper-LDL emia) was 9.8%, 24.4%, 12.3% and 27.9%. The prevalence of hypercholesterolemia was 11.2%, 23.5%, 14.7%, 28.5% and the prevalence of hyperglycemia was 9.7%, 22.6%, 18.5%, and 27.0%, respectively. The prevalence of hypertension was 6.9%, 13.1%, 14.7%, and 20.6%. For various metabolic abnormalities, OBCO have the highest risks compared with NW (hyperuricemia: adjusted OR (aOR)= 2.60; hypertriglyceridemia: aOR= 3.19; hypercholesterolemia: aOR= 1.48; hyper LDLemia: aOR= 2.21; hypo HDLemia: aOR= 1.42; hyperglycemia: aOR= 1.95; hypertension: aOR= 2.16). The risk of hyper LDLemia, hypercholesterolemia and hyperglycemia in the NWCO group was higher than that in the OB group (hyperLDLemia: aOR: 1.69 vs 0.97; hypercholesterolemia: aOR: 1.27 vs 1.24; hyperglycemia: aOR: 1.62 vs 1.28). CONCLUSION Different phenotypes of obesity are significantly associated with metabolic abnormalities. NWCO is more closely associated with hypercholesterolemia, hyperglycemia and hyper LDLemia. General obesity and central obesity have a synergistic effect on the diseases.
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Affiliation(s)
- Xixuan Lu
- Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, Yinchuan, Ningxia, People’s Republic of China
- Correspondence: Xixuan Lu Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, No. 804, Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, People’s Republic of ChinaTel +860951-6746645 Email
| | - Qiang Wang
- Department of Medical Office, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, People’s Republic of China
| | - Haiyan Liang
- Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, Yinchuan, Ningxia, People’s Republic of China
| | - Li Xu
- Department of Radiology, People’s Liberation Army’s Joint Service for the 942nd Hospital, Yinchuan, Ningxia, People’s Republic of China
| | - Liping Sha
- Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, Yinchuan, Ningxia, People’s Republic of China
| | - Yuemei Wu
- Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, Yinchuan, Ningxia, People’s Republic of China
| | - Liting Ma
- Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, Yinchuan, Ningxia, People’s Republic of China
| | - Ping Yang
- Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, Yinchuan, Ningxia, People’s Republic of China
| | - Hong Lei
- Department of Endocrinology, Cardiovascular and Cerebrovascular Disease Hospital, Ningxia Medical University General Hospital, Yinchuan, Ningxia, People’s Republic of China
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Liu F, He J, Wang H, Zhu D, Bi Y. Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction. Obes Surg 2020; 30:5086-5100. [PMID: 33021706 PMCID: PMC7719100 DOI: 10.1007/s11695-020-04983-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/30/2022]
Abstract
Emerging evidence highlights that dysfunction of adipose tissue contributes to impaired insulin sensitivity and systemic metabolic deterioration in obese state. Of note, adipocyte hypertrophy serves as a critical event which associates closely with adipose dysfunction. An increase in cell size exacerbates hypoxia and inflammation as well as excessive collagen deposition, finally leading to metabolic dysregulation. Specific mechanisms of adipocyte hypertrophy include dysregulated differentiation and maturation of preadipocytes, enlargement of lipid droplets, and abnormal adipocyte osmolarity sensors. Also, weight loss therapies exert profound influence on adipocyte size. Here, we summarize the critical role of adipocyte hypertrophy in the development of metabolic disturbances. Future studies are required to establish a standard criterion of size measurement to better clarify the impact of adipocyte hypertrophy on changes in metabolic homeostasis.
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Affiliation(s)
- Fangcen Liu
- Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College, Nanjing Medical University, Nanjing, China
| | - Jielei He
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Hongdong Wang
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Dalong Zhu
- Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College, Nanjing Medical University, Nanjing, China
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yan Bi
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
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Cox AR, Chernis N, Bader DA, Saha PK, Masschelin PM, Felix JB, Sharp R, Lian Z, Putluri V, Rajapakshe K, Kim KH, Villareal DT, Armamento-Villareal R, Wu H, Coarfa C, Putluri N, Hartig SM. STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity. Diabetes 2020; 69:2630-2641. [PMID: 32994273 PMCID: PMC7679774 DOI: 10.2337/db20-0384] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022]
Abstract
Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 a-KO ) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1 a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.
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Affiliation(s)
- Aaron R Cox
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Natasha Chernis
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - David A Bader
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Pradip K Saha
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Peter M Masschelin
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Jessica B Felix
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Robert Sharp
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Zeqin Lian
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Vasanta Putluri
- Dan L. Duncan Comprehensive Cancer Center, Advanced Technology Cores, Baylor College of Medicine, Houston, TX
| | - Kimal Rajapakshe
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Advanced Technology Cores, Baylor College of Medicine, Houston, TX
| | - Kang Ho Kim
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Dennis T Villareal
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
- Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, TX
| | - Reina Armamento-Villareal
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
- Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, TX
| | - Huaizhu Wu
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Advanced Technology Cores, Baylor College of Medicine, Houston, TX
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Advanced Technology Cores, Baylor College of Medicine, Houston, TX
| | - Sean M Hartig
- Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
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F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes. Int J Obes (Lond) 2020; 45:577-587. [PMID: 33221826 DOI: 10.1038/s41366-020-00722-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/10/2020] [Accepted: 11/05/2020] [Indexed: 11/08/2022]
Abstract
OBJECTIVE F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. METHODS We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. RESULTS F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. CONCLUSIONS F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.
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Gharanei S, Shabir K, Brown JE, Weickert MO, Barber TM, Kyrou I, Randeva HS. Regulatory microRNAs in Brown, Brite and White Adipose Tissue. Cells 2020; 9:cells9112489. [PMID: 33207733 PMCID: PMC7696849 DOI: 10.3390/cells9112489] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/02/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA, inducing translational repression and messenger RNA degradation. This regulation of gene expression by miRNAs in adipose tissue (AT) can impact on the regulation of metabolism and energy homeostasis, particularly considering the different types of adipocytes which exist in mammals, i.e., white adipocytes (white AT; WAT), brown adipocytes (brown AT; BAT), and inducible brown adipocytes in WAT (beige or brite or brown-in-white adipocytes). Indeed, an increasing number of miRNAs has been identified to regulate key signaling pathways of adipogenesis in BAT, brite AT, and WAT by acting on transcription factors that promote or inhibit adipocyte differentiation. For example, MiR-328, MiR-378, MiR-30b/c, MiR-455, MiR-32, and MiR-193b-365 activate brown adipogenesis, whereas MiR-34a, MiR-133, MiR-155, and MiR-27b are brown adipogenesis inhibitors. Given that WAT mainly stores energy as lipids, whilst BAT mainly dissipates energy as heat, clarifying the effects of miRNAs in different types of AT has recently attracted significant research interest, aiming to also develop novel miRNA-based therapies against obesity, diabetes, and other obesity-related diseases. Therefore, this review presents an up-to-date comprehensive overview of the role of key regulatory miRNAs in BAT, brite AT, and WAT.
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Affiliation(s)
- Seley Gharanei
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Kiran Shabir
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
| | - James E. Brown
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
| | - Martin O. Weickert
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Centre of Applied Biological & Exercise Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
| | - Thomas M. Barber
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK; (S.G.); (M.O.W.); (T.M.B.); (I.K.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK; (K.S.); (J.E.B.)
- Correspondence:
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Pope BD, Warren CR, Dahl MO, Pizza CV, Henze DE, Sinatra NR, Gonzalez GM, Chang H, Liu Q, Glieberman AL, Ferrier JP, Cowan CA, Parker KK. Fattening chips: hypertrophy, feeding, and fasting of human white adipocytes in vitro. LAB ON A CHIP 2020; 20:4152-4165. [PMID: 33034335 PMCID: PMC7818847 DOI: 10.1039/d0lc00508h] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Adipose is a distributed organ that performs vital endocrine and energy homeostatic functions. Hypertrophy of white adipocytes is a primary mode of both adaptive and maladaptive weight gain in animals and predicts metabolic syndrome independent of obesity. Due to the failure of conventional culture to recapitulate adipocyte hypertrophy, technology for production of adult-size adipocytes would enable applications such as in vitro testing of weight loss therapeutics. To model adaptive adipocyte hypertrophy in vitro, we designed and built fat-on-a-chip using fiber networks inspired by extracellular matrix in adipose tissue. Fiber networks extended the lifespan of differentiated adipocytes, enabling growth to adult sizes. By micropatterning preadipocytes in a native cytoarchitecture and by adjusting cell-to-cell spacing, rates of hypertrophy were controlled independent of culture time or differentiation efficiency. In vitro hypertrophy followed a nonlinear, nonexponential growth model similar to human development and elicited transcriptomic changes that increased overall similarity with primary tissue. Cells on the chip responded to simulated meals and starvation, which potentiated some adipocyte endocrine and metabolic functions. To test the utility of the platform for therapeutic development, transcriptional network analysis was performed, and retinoic acid receptors were identified as candidate drug targets. Regulation by retinoid signaling was suggested further by pharmacological modulation, where activation accelerated and inhibition slowed hypertrophy. Altogether, this work presents technology for mature adipocyte engineering, addresses the regulation of cell growth, and informs broader applications for synthetic adipose in pharmaceutical development, regenerative medicine, and cellular agriculture.
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Affiliation(s)
- Benjamin D Pope
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA. and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Curtis R Warren
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Madeleine O Dahl
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Christina V Pizza
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Douglas E Henze
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Nina R Sinatra
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Grant M Gonzalez
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Huibin Chang
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Qihan Liu
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Aaron L Glieberman
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - John P Ferrier
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA.
| | - Chad A Cowan
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Kevin Kit Parker
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Pierce Hall, Room 318, 29 Oxford Street, Cambridge, MA 02138, USA. and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
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DeBari MK, Abbott RD. Adipose Tissue Fibrosis: Mechanisms, Models, and Importance. Int J Mol Sci 2020; 21:ijms21176030. [PMID: 32825788 PMCID: PMC7503256 DOI: 10.3390/ijms21176030] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/15/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Increases in adipocyte volume and tissue mass due to obesity can result in inflammation, further dysregulation in adipose tissue function, and eventually adipose tissue fibrosis. Like other fibrotic diseases, adipose tissue fibrosis is the accumulation and increased production of extracellular matrix (ECM) proteins. Adipose tissue fibrosis has been linked to decreased insulin sensitivity, poor bariatric surgery outcomes, and difficulty in weight loss. With the rising rates of obesity, it is important to create accurate models for adipose tissue fibrosis to gain mechanistic insights and develop targeted treatments. This article discusses recent research in modeling adipose tissue fibrosis using in vivo and in vitro (2D and 3D) methods with considerations for biomaterial selections. Additionally, this article outlines the importance of adipose tissue in treating other fibrotic diseases and methods used to detect and characterize adipose tissue fibrosis.
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Affiliation(s)
- Megan K. DeBari
- Department of Materials Science and Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA;
| | - Rosalyn D. Abbott
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Correspondence:
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Perrone MA, Babu Dasari J, Intorcia A, Gualtieri P, Marche M, Di Luozzo M, Merra G, Bernardini S, Romeo F, Sergi D. Phenotypic classification and biochemical profile of obesity for cardiovascular prevention. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2020. [DOI: 10.23736/s0393-3660.20.04259-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Jarvie EM, Stewart FM, Ramsay JE, Brown EA, Meyer BJ, Olivecrona G, Griffin BA, Freeman DJ. Maternal Adipose Tissue Expansion, A Missing Link in the Prediction of Birth Weight Centile. J Clin Endocrinol Metab 2020; 105:5674932. [PMID: 31832635 DOI: 10.1210/clinem/dgz248] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/12/2019] [Indexed: 12/17/2022]
Abstract
CONTEXT Maternal body mass index (BMI) is associated with increased birth weight but does not explain all the variance in fetal adiposity. OBJECTIVE To assess the contribution of maternal body fat distribution to offspring birth weight and adiposity. DESIGN Longitudinal study throughout gestation and at delivery. SETTING Women recruited at 12 weeks of gestation and followed up at 26 and 36 weeks. Cord blood was collected at delivery. PATIENTS Pregnant women (n = 45) with BMI 18.0 to 46.3 kg/m2 and healthy pregnancy outcome. METHODS Maternal first trimester abdominal subcutaneous and visceral adipose tissue thickness (SAT and VAT) was assessed by ultrasound. MAIN OUTCOME MEASURES Maternal body fat distribution, maternal and cord plasma glucose and lipid concentrations, placental weight, birth weight, and fetal adiposity assessed by cord blood leptin. RESULTS VAT was the only anthropometric measure independently associated with birth weight centile (r2 adjusted 15.8%, P = .002). BMI was associated with trimester 2 and trimesters 1 through 3 area under the curve (AUC) glucose and insulin resistance (Homeostatic Model Assessment). SAT alone predicted trimester 2 lipoprotein lipase (LPL) mass (a marker of adipocyte insulin sensitivity) (11.3%, P = .017). VAT was associated with fetal triglyceride (9.3%, P = .047). Placental weight was the only independent predictor of fetal adiposity (48%, P < .001). Maternal trimester 2 and AUC LPL were inversely associated with fetal adiposity (r = -0.69, P = .001 and r = -0.58, P = .006, respectively). CONCLUSIONS Maternal VAT provides additional information to BMI for prediction of birth weight. VAT may be a marker of reduced SAT expansion and increased availability of maternal fatty acids for placental transport.
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Affiliation(s)
- Eleanor M Jarvie
- Institute of Cardiovascular and Me dical Sciences, University of Glasgow, Glasgow, UK
| | | | - Jane E Ramsay
- School of Medicine, University of Glasgow, Glasgow, UK
| | - E Ann Brown
- School of Medicine, University of Glasgow, Glasgow, UK
| | - Barbara J Meyer
- School of Medicine, Lipid Research Centre, Molecular Horizons, University of Wollongong, Illawara Health & Medical Research Institute, Wollongong, Australia
| | | | - Bruce A Griffin
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Dilys J Freeman
- Institute of Cardiovascular and Me dical Sciences, University of Glasgow, Glasgow, UK
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Aitken-Buck HM, Moharram M, Babakr AA, Reijers R, Van Hout I, Fomison-Nurse IC, Sugunesegran R, Bhagwat K, Davis PJ, Bunton RW, Williams MJA, Stiles MK, Jones PP, Coffey S, Lamberts RR. Relationship between epicardial adipose tissue thickness and epicardial adipocyte size with increasing body mass index. Adipocyte 2019; 8:412-420. [PMID: 31829077 PMCID: PMC6948959 DOI: 10.1080/21623945.2019.1701387] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Macroscopic deposition of epicardial adipose tissue (EAT) has been strongly associated with numerous indices of obesity and cardiovascular disease risk. In contrast, the morphology of EAT adipocytes has rarely been investigated. We aimed to determine whether obesity-driven adipocyte hypertrophy, which is characteristic of other visceral fat depots, is found within EAT adipocytes. EAT samples were collected from cardiac surgery patients (n = 49), stained with haematoxylin & eosin, and analysed for mean adipocyte size and non-adipocyte area. EAT thickness was measured using echocardiography. A significant positive relationship was found between EAT thickness and body mass index (BMI). When stratified into standardized BMI categories, EAT thickness was 58.7% greater (p = 0.003) in patients from the obese (7.3 ± 1.8 mm) compared to normal (4.6 ± 0.9 mm) category. BMI as a continuous variable significantly correlated with EAT thickness (r = 0.56, p < 0.0001). Conversely, no correlation was observed between adipocyte size and either BMI or EAT thickness. No difference in the non-adipocyte area was found between BMI groups. Our results suggest that the increased macroscopic EAT deposition associated with obesity is not caused by adipocyte hypertrophy. Rather, alternative remodelling via adipocyte proliferation might be responsible for the observed EAT expansion.
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Affiliation(s)
- Hamish M. Aitken-Buck
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Mohammed Moharram
- Department of Medicine, HeartOtago, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand
| | - Aram A Babakr
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Robin Reijers
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Isabelle Van Hout
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Ingrid C. Fomison-Nurse
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Ramanen Sugunesegran
- Department of Cardiothoracic Surgery, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand
| | - Krishna Bhagwat
- Department of Cardiothoracic Surgery, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand
| | - Phillip J Davis
- Department of Cardiothoracic Surgery, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand
| | - Richard W. Bunton
- Department of Cardiothoracic Surgery, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand
| | - Michael J. A. Williams
- Department of Medicine, HeartOtago, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand
| | - Martin K. Stiles
- Department of Cardiology, Waikato District Health Board, Hamilton, New Zealand
- Waikato Clinical School, University of Auckland, Hamilton, New Zealand
| | - Peter P. Jones
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Sean Coffey
- Department of Medicine, HeartOtago, Dunedin School of Medicine, Dunedin Hospital, Dunedin, New Zealand
| | - Regis R. Lamberts
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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Abstract
PURPOSE OF REVIEW Obesity is a major risk factor for type 2 diabetes. Although adipose tissue allows storage of excess calories in periods of overnutrition, in obesity, adipose tissue metabolism becomes dysregulated and can promote metabolic diseases. This review discusses recent advances in understandings how adipocyte metabolism impacts metabolic homeostasis. RECENT FINDINGS The ability of adipocytes to synthesize lipids from glucose is a marker of metabolic fitness, e.g., low de novo lipogenesis (DNL) in adipocytes correlates with insulin resistance in obesity. Adipocyte DNL may promote synthesis of special "insulin sensitizing" signaling lipids that act hormonally. However, each metabolic intermediate in the DNL pathway (i.e., citrate, acetyl-CoA, malonyl-CoA, and palmitate) also has second messenger functions. Mounting evidence suggests these signaling functions may also be important for maintaining healthy adipocytes. While adipocyte DNL contributes to lipid storage, lipid precursors may have additional second messenger functions critical for maintaining adipocyte health, and thus systemic metabolic homeostasis.
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Affiliation(s)
- Wen-Yu Hsiao
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA, 01605, USA
| | - David A Guertin
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA, 01605, USA.
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Aitken-Buck HM, Babakr AA, Coffey S, Jones PP, Tse RD, Lamberts RR. Epicardial adipocyte size does not correlate with body mass index. Cardiovasc Pathol 2019; 43:107144. [DOI: 10.1016/j.carpath.2019.07.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/18/2019] [Accepted: 07/29/2019] [Indexed: 12/31/2022] Open
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Cox AR, Chernis N, Masschelin PM, Hartig SM. Immune Cells Gate White Adipose Tissue Expansion. Endocrinology 2019; 160:1645-1658. [PMID: 31107528 PMCID: PMC6591013 DOI: 10.1210/en.2019-00266] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/14/2019] [Indexed: 12/15/2022]
Abstract
The immune system plays a critical role in white adipose tissue (WAT) energy homeostasis and, by extension, whole-body metabolism. Substantial evidence from mouse and human studies firmly establishes that insulin sensitivity deteriorates as a result of subclinical inflammation in the adipose tissue of individuals with diabetes. However, the relationship between adipose tissue expandability and immune cell infiltration remains a complex problem important for understanding the pathogenesis of obesity. Notably, a large body of work challenges the idea that all immune responses are deleterious to WAT function. This review highlights recent advances that describe how immune cells and adipocytes coordinately enable WAT expansion and regulation of energy homeostasis.
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Affiliation(s)
- Aaron R Cox
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Natasha Chernis
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Peter M Masschelin
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Sean M Hartig
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Correspondence: Sean M. Hartig, PhD, Baylor College of Medicine, One Baylor Plaza, BCM185, Houston, Texas 77030. E-mail:
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Baker HA, Fabian CJ, Hastings RC, Dixon DA, Nydegger JL, Phillips TA, Powers KR, Kimler BF. Circulating adipose stromal cells as a response biomarker in phase II energy balance trials of obese breast cancer survivors and high-risk women. Breast Cancer Res Treat 2019; 176:387-394. [PMID: 31041685 DOI: 10.1007/s10549-019-05251-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 04/22/2019] [Indexed: 01/09/2023]
Abstract
PURPOSE Circulating adipose stromal cells (CASC) are thought to be increased in obesity and facilitate angiogenesis, and tumor metastases. METHODS CASC were identified from buffy coat peripheral blood mononuclear cells (PBMCs) by flow cytometry as CD34brightCD31- CD45- and CASC frequency was compared to adiposity measures in 33 women at increased risk for breast cancer. Feasibility of CASC as a response biomarker for a diet and exercise intervention in ten breast cancer survivors was then explored. RESULTS For 33 high-risk women, median CASC frequency was 9.7 per million PBMCs and trended positively with body mass index, fat mass index (FMI), and percent android fat. Correlation was significant when BMI was dichotomized at > versus < 35 kg/m2 (p = 0.02). For ten breast cancer survivors with a median BMI of 37 kg/m2, median CASC frequency was 16.4 per million PBMCs. In univariate analyses, change in BMI, total fat and visceral fat were significantly correlated with change in CASC frequency. On multivariate analysis, change in visceral adipose had the strongest association with change in CASC frequency (p < 0.00078). CONCLUSIONS The association between the reduction in visceral adipose tissue and the decrease in frequency of circulating adipose stromal cells suggests that the latter might be a useful biomarker in clinical trials of obese breast cancer survivors undergoing a weight loss intervention.
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Affiliation(s)
- Hailey A Baker
- University of Kansas School of Medicine-Wichita, 1010 N Kansas St., Wichita, KS, 67214, USA
| | - Carol J Fabian
- Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
| | - Richard C Hastings
- Flow Cytometry Core Laboratory, Department of Microbiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Dan A Dixon
- Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence, KS, 66045, USA
| | - Jennifer L Nydegger
- Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Teresa A Phillips
- Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Kandy R Powers
- Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
| | - Bruce F Kimler
- Department of Radiation Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
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Kerr AG, Sinha I, Dadvar S, Arner P, Dahlman I. Epigenetic regulation of diabetogenic adipose morphology. Mol Metab 2019; 25:159-167. [PMID: 31031182 PMCID: PMC6600120 DOI: 10.1016/j.molmet.2019.04.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 04/13/2019] [Indexed: 12/17/2022] Open
Abstract
Objective Hypertrophic white adipose tissue (WAT) morphology is associated with insulin resistance and type 2 diabetes. The mechanisms governing hyperplastic versus hypertrophic WAT expansion are poorly understood. We assessed if epigenetic modifications in adipocytes are associated with hypertrophic adipose morphology. A subset of genes with differentially methylated CpG-sites (DMS) in the promoters was taken forward for functional evaluation. Methods The study included 126 women who underwent abdominal subcutaneous biopsy to determine adipose morphology. Global transcriptome profiling was performed on WAT from 113 of the women, and CpG methylome profiling on isolated adipocytes from 78 women. Small interfering RNAs (siRNA) knockdown in human mesenchymal stem cells (hMSCs) was used to assess influence of specific genes on lipid storage. Results A higher proportion of CpG-sites were methylated in hypertrophic compared to hyperplastic WAT. Methylation at 35,138 CpG-sites was found to correlate to adipose morphology. 2,102 of these CpG-sites were also differentially methylated in T2D; 98% showed directionally consistent change in methylation in WAT hypertrophy and T2D. We identified 2,508 DMS in 638 adipose morphology-associated genes where methylation correlated with gene expression. These genes were over-represented in gene sets relevant to WAT hypertrophy, such as insulin resistance, lipolysis, extracellular matrix organization, and innate immunity. siRNA knockdown of ADH1B, AZGP1, C14orf180, GYG2, HADH, PRKAR2B, PFKFB3, and AQP7 influenced lipid storage and metabolism. Conclusion CpG methylation could be influential in determining adipose morphology and thereby constitute a novel antidiabetic target. We identified C14orf180 as a novel regulator of adipocyte lipid storage and possibly differentiation.
Hypertrophic adipose morphology display a distinct adipocyte CpG-methylome profile. Adipose hypertrophy and type 2 diabetes display strong overlap in CpG-methylome profile. C14orf180 is a novel regulator of adipocyte lipid storage and possibly adipogenesis.
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Affiliation(s)
- A G Kerr
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - I Sinha
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - S Dadvar
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - P Arner
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - I Dahlman
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
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Louis F, Kitano S, Mano JF, Matsusaki M. 3D collagen microfibers stimulate the functionality of preadipocytes and maintain the phenotype of mature adipocytes for long term cultures. Acta Biomater 2019; 84:194-207. [PMID: 30502481 DOI: 10.1016/j.actbio.2018.11.048] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 11/26/2018] [Accepted: 11/27/2018] [Indexed: 12/28/2022]
Abstract
Although adipose tissue is one of the most abundant tissues of the human body, its reconstruction remains a competitive challenge. The conventional in vitro two or three-dimensional (2D or 3D) models of mature adipocytes unfortunately lead to their quick dedifferentiation after one week, and complete differentiation of adipose derived stem cells (ADSC) usually requires more than one month. In this context, we developed biomimetic 3D adipose tissues with high density collagen by mixing type I collagen microfibers with primary mouse mature adipocytes or human ADSC in transwells. These 3D-tissues ensured a better long-term maintained phenotype of unilocular mature adipocytes, compared to 2D, with a viability of 96 ± 2% at day 14 and a good perilipin immunostaining, - the protein necessary for stabilizing the fat vesicles. For comparison, in 2D culture, mature adipocytes released their fat until splitting their single adipose vesicle into several ones with significantly 4 times smaller size. Concerning ADSC, the adipogenic genes expression in 3D-tissues was found at least doubled throughout the differentiation (over 8 times higher for GLUT4 at day 21), along with it, almost 4 times larger fat vesicles were observed (10 ± 4 µm at day 14). Perilipin immunostaining and leptin secretion, the satiety protein, attested the significantly doubled better functionality of ADSC in 3D adipose tissues. These obtained long-term maintained phenotype and fast adipogenesis make this model relevant for either cosmetic/pharmaceutical assays or plastic surgery purposes. STATEMENT OF SIGNIFICANCE: Adipose tissue has important roles in our organism, providing energy from its lipids storage and secreting many vital proteins. However, its reconstruction in a functional in vitro adipose tissue is still a challenge. Mature adipocytes directly extracted from surgery liposuctions quickly lose their lipids after a week in vitro and the use of differentiated adipose stem cells is too time-consuming. We developed a new artificial fat tissue using collagen microfibers. These tissues allowed the maintenance of viable big unilocular mature adipocytes up to two weeks and the faster adipogenic differentiation of adipose stem cells. Moreover, the adipose functionality confirmed by perilipin and leptin assessments makes this model suitable for further applications in cosmetic/pharmaceutical drug assays or for tissue reconstruction.
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Affiliation(s)
- Fiona Louis
- Osaka University, Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Japan
| | - Shiro Kitano
- Osaka University, Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Japan
| | - João F Mano
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Portugal
| | - Michiya Matsusaki
- Osaka University, Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Japan; Division of Applied Chemistry, Graduate School of Engineering, Osaka University, Japan; JST, PRESTO, Japan.
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49
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Hammarstedt A, Gogg S, Hedjazifar S, Nerstedt A, Smith U. Impaired Adipogenesis and Dysfunctional Adipose Tissue in Human Hypertrophic Obesity. Physiol Rev 2019; 98:1911-1941. [PMID: 30067159 DOI: 10.1152/physrev.00034.2017] [Citation(s) in RCA: 302] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor cells. When inadequate, this leads to a hypertrophic expansion of the cells with increased inflammation, insulin resistance, and a dysfunctional prolipolytic tissue. Epi-/genetic factors regulate SAT adipogenesis and genetic predisposition for type 2 diabetes is associated with markers of an impaired SAT adipogenesis and development of hypertrophic obesity also in nonobese individuals. We here review mechanisms for the adipose precursor cells to enter adipogenesis, emphasizing the role of bone morphogenetic protein-4 (BMP-4) and its endogenous antagonist gremlin-1, which is increased in hypertrophic SAT in humans. Gremlin-1 is a secreted and a likely important mechanism for the impaired SAT adipogenesis in hypertrophic obesity. Transiently increasing BMP-4 enhances adipogenic commitment of the precursor cells while maintained BMP-4 signaling during differentiation induces a beige/brown oxidative phenotype in both human and murine adipose cells. Adipose tissue growth and development also requires increased angiogenesis, and BMP-4, as a proangiogenic molecule, may also be an important feedback regulator of this. Hypertrophic obesity is also associated with increased lipolysis. Reduced lipid storage and increased release of FFA by hypertrophic SAT are important mechanisms for the accumulation of ectopic fat in the liver and other places promoting insulin resistance. Taken together, the limited expansion and storage capacity of SAT is a major driver of the obesity-associated metabolic complications.
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Affiliation(s)
- Ann Hammarstedt
- Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, the Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Silvia Gogg
- Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, the Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Shahram Hedjazifar
- Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, the Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Annika Nerstedt
- Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, the Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Ulf Smith
- Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, the Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
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Amiri P, Naghizadeh M, Baradaran B, Saghafi-Asl M, Shanehbandi D, Mirmajidi S. Insulin resistance in relation to inflammatory gene expression and metabolic features in apparently healthy obese individuals. Int J Diabetes Dev Ctries 2019. [DOI: 10.1007/s13410-018-0626-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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