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1
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Kruglikov IL, Scherer PE. Regulation of the terminal complement cascade in adipose tissue for control of its volume, cellularity, and fibrosis. Obesity (Silver Spring) 2025; 33:839-850. [PMID: 40134146 PMCID: PMC12015659 DOI: 10.1002/oby.24270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/28/2024] [Accepted: 01/26/2025] [Indexed: 03/27/2025]
Abstract
White adipose tissue (WAT) is a reservoir for various pathogens and their products, such as lipopolysaccharides. Therefore, it must be equipped with a defense mechanism connected with the activation of innate immunity. This explains the phenomenon that adipocytes express components of the classical and alternative complement pathways, which can be activated even in the absence of opportunistic pathogens. Terminal stages of the complement pathway are related to the production of membrane attack complexes and, thus, can cause lysis of pathogens, as well as autolysis of host adipocytes, contributing to the regulation of the cellularity in WAT. Complement-induced autolysis of adipocytes is counteracted by a number of cellular defense mechanisms. This versatility of activation and suppression processes enables a broad range of adaptability to physiological contexts, ranging from the development of hypertrophic WAT to lipodystrophy. Pathogen-induced activation of the complement pathway in WAT also induces a profibrotic phenotype. These processes may also be involved in the regulation of insulin resistance in adipocytes. This explains the dual immune/metabolic role of the complement pathway in WAT: the pathway is an integral part of the immune response but also potently involved in the control of volume and cellularity of WAT under both physiological and pathological conditions.
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Affiliation(s)
| | - Philipp E. Scherer
- Touchstone Diabetes CenterUniversity of Texas Southwestern Medical CenterDallasTexasUSA
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2
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Hsu JCN, Chiu KT, Chen CH, Wang CH, Shyue SK, Lee TS. HMGB1 Regulates Adipocyte Lipolysis via Caveolin-1 Signaling: Implications for Metabolic and Cardiovascular Diseases. Int J Mol Sci 2025; 26:4222. [PMID: 40362460 PMCID: PMC12071352 DOI: 10.3390/ijms26094222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/24/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
High-mobility group box 1 (HMGB1) is a nuclear protein that can be secreted or released into the extracellular environment during cellular stress, functioning as a damage-associated molecular pattern molecule. This study investigates the role of HMGB1 in adipocyte development and metabolism, explicitly examining its interaction with β3-adrenergic receptor-mediated lipolysis and caveolin-1 (CAV1) regulation, which may influence cardiovascular risk factors. Using 3T3-L1 preadipocytes and mouse embryonic fibroblasts, we demonstrated that HMGB1 expression increases progressively during adipogenesis, reaching peak levels in mature adipocytes. While exogenous HMGB1 treatment did not affect preadipocyte proliferation or differentiation, it inhibited lipolysis in mature adipocytes. Mechanistically, HMGB1 suppressed β3-adrenergic receptor agonist CL-316,243-induced hormone-sensitive lipase activation by reducing protein kinase A-mediated phosphorylation and attenuating extracellular signal-regulated kinase signaling without affecting upstream cyclic AMP levels. We discovered a novel regulatory mechanism wherein CAV1 physically interacts with HMGB1 in mature adipocytes, with c-Src-dependent CAV1 phosphorylation functioning as a negative regulator of HMGB1 secretion. This finding was confirmed in CAV1-deficient models, which displayed increased HMGB1 secretion and diminished lipolytic activity both in vitro and in vivo. Furthermore, administering HMGB1-neutralizing antibodies to wild-type mice enhanced fasting-induced lipolysis, establishing circulating HMGB1 as a crucial antilipolytic factor. These findings reveal HMGB1's previously uncharacterized role in adipose tissue metabolism as a negative regulator of lipolysis through CAV1-dependent mechanisms. This work provides new insights into adipose tissue metabolism regulation and identifies potential therapeutic targets for obesity-related metabolic disorders and cardiovascular diseases.
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Affiliation(s)
- Julia Chu-Ning Hsu
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, 145, Xingda Road, South District, Taichung 402202, Taiwan;
| | - Kuan-Ting Chiu
- Department of Physiology, School of Medicine, National Yang-Ming University, 155, Sec. 2, Linong Street, Beitou District, Taipei 112304, Taiwan
| | - Chia-Hui Chen
- Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, 1, Sec. 1, Jenai Road, Zhongzheng District, Taipei 100233, Taiwan
| | - Chih-Hsien Wang
- Cardiovascular Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, 7, Chungshan South Road, Zhongzheng District, Taipei 100225, Taiwan
| | - Song-Kun Shyue
- Institute of Biomedical Sciences, Academia Sinica, 128, Sec. 2, Academia Road, Nankang District, Taipei 115201, Taiwan
| | - Tzong-Shyuan Lee
- Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, 1, Sec. 1, Jenai Road, Zhongzheng District, Taipei 100233, Taiwan
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3
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Hansen D, Jensen JER, Andersen CAT, Jakobsgaard PR, Havelund J, Lauritsen L, Mandacaru S, Siersbaek M, Shackleton OL, Inoue H, Brewer JR, Schwabe RF, Blagoev B, Færgeman NJ, Salmi M, Ravnskjaer K. Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein. Cell Metab 2025; 37:971-986.e8. [PMID: 40037362 DOI: 10.1016/j.cmet.2025.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 11/26/2024] [Accepted: 01/24/2025] [Indexed: 03/06/2025]
Abstract
The liver is essential for normal fatty acid utilization during fasting. Circulating fatty acids are taken up by hepatocytes and esterified as triacylglycerols for either oxidative metabolization and ketogenesis or export. Whereas the regulation of fatty acid oxidation in hepatocytes is well understood, the uptake and retention of non-esterified fatty acids by hepatocytes is not. Here, we show that murine hepatic stellate cells (HSCs) and their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control hepatic substrate preference for fasting energy metabolism. HSC-specific ablation of PLVAP in mice elevated hepatic insulin signaling and improved glucose tolerance. Fasted HSC PLVAP knockout mice showed suppressed hepatic fatty acid esterification into di- and triacylglycerols, shifting fasting metabolism from fatty acid oxidation to reliance on carbohydrates. By super-resolution microscopy, we localized HSC PLVAP to caveolae residing along the sinusoidal lumen, supporting a role for HSCs and PLVAP-diaphragmed caveolae in normal fasting metabolism of the liver.
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Affiliation(s)
- Daniel Hansen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Jasmin E R Jensen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Christian A T Andersen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Peter R Jakobsgaard
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Jesper Havelund
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Line Lauritsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Samuel Mandacaru
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Majken Siersbaek
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Oliver L Shackleton
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan
| | - Jonathan R Brewer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Blagoy Blagoev
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Nils J Færgeman
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Marko Salmi
- MediCity Research Laboratory, University of Turku, 20014 Turku, Finland; Institute of Biomedicine, University of Turku, 20014 Turku, Finland; InFLAMES Research Flagship Centre, University of Turku, 20014 Turku, Finland
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark.
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4
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Rodriguez SYV, Lazaridis T. Seeking the Membrane-Bound Structure of the Caveolin 8S Complex. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.09.642159. [PMID: 40161753 PMCID: PMC11952317 DOI: 10.1101/2025.03.09.642159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The protein caveolin-1 (CAV1) is essential in the generation of caveolae, cup-like invaginations in the plasma membrane, but the mechanism of its action remains unclear. A recent cryo-EM structure showed an 11-mer of CAV1 (the 8S complex) forming a disk with a flat membrane-facing surface, raising the question of how a flat complex is able to generate membrane curvature. We previously conducted implicit-solvent molecular dynamics simulations, which showed the 8S complex adopting a conical shape, with its outer ridge deep inside the implicit membrane. These results suggested a scaffolding-type mechanism for curvature generation by the 8S complex. In this work we aimed to validate this proposal via all-atom simulations. To date, all simulations (other than in vacuum) show the complex taking a conical shape. The arrangement of lipids around the complex depends on the starting configuration. Starting on top of the bilayer leads to lipid extraction and water molecules trapped between the 8S complex and the bilayer, creating a protrusion on the distal leaflet. Starting deep inside the bilayer, displacing the proximal leaflet, leads to a more plausible configuration with the distal leaflet lipids adsorbed onto the 8S concave surface. Further work is needed to characterize the determinants of 8S shape and its membrane curvature generating capabilities, as well as the role of lipid composition.
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Affiliation(s)
| | - Themis Lazaridis
- Department of Chemistry, City College of New York/CUNY, 160 Convent Ave, New York, NY 10031, USA; Graduate Programs in Chemistry, Biochemistry, and Physics, The Graduate Center, City University of New York,365 Fifth Ave., New York, NY 10016, USA
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5
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Aboy-Pardal MCM, Guadamillas MC, Guerrero CR, Català-Montoro M, Toledano-Donado M, Terrés-Domínguez S, Pavón DM, Jiménez-Jiménez V, Jimenez-Carretero D, Zamai M, Folgueira C, Cerezo A, Lolo FN, Nogueiras R, Sabio G, Sánchez-Álvarez M, Echarri A, Garcia R, Del Pozo MA. Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability. Nat Commun 2024; 15:10102. [PMID: 39609408 PMCID: PMC11605069 DOI: 10.1038/s41467-024-54224-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 11/05/2024] [Indexed: 11/30/2024] Open
Abstract
Adipocytes expand massively to accommodate excess energy stores and protect the organism from lipotoxicity. Adipose tissue expandability is at the center of disorders such as obesity and lipodystrophy; however, little is known about the relevance of adipocyte biomechanics on the etiology of these conditions. Here, we show in male mice in vivo that the adipocyte plasma membrane undergoes caveolar domain reorganization upon lipid droplet expansion. As the lipid droplet grows, caveolae disassemble to release their membrane reservoir and increase cell surface area, and transfer specific caveolar components to the LD surface. Adipose tissue null for caveolae is stiffer, shows compromised deformability, and is prone to rupture under mechanical compression. Mechanistically, phosphoacceptor Cav1 Tyr14 is required for caveolae disassembly: adipocytes bearing a Tyr14Phe mutation at this residue are stiffer and smaller, leading to decreased adiposity in vivo; exhibit deficient transfer of Cav1 and EHD2 to the LD surface, and show distinct Cav1 molecular dynamics and tension adaptation. These results indicate that Cav1 phosphoregulation modulates caveolar dynamics as a relevant component of the homeostatic mechanoadaptation of the differentiated adipocyte.
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Affiliation(s)
- María C M Aboy-Pardal
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Marta C Guadamillas
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Department of Science and Agroforestal Technology and Genetics, Faculty of Biochemistry and Environmental Sciences, University of Castilla-La Mancha, Toledo, Spain
| | - Carlos R Guerrero
- ForceTool group, Instituto de Ciencia de Materiales de Madrid (ICMM), CSIC, Madrid, Spain
| | - Mauro Català-Montoro
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Mónica Toledano-Donado
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Sara Terrés-Domínguez
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Dácil M Pavón
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Allergy Therapeutics, Avenida Punto Es, 12, 28805 Alcalá de Henares, Madrid, Spain
| | - Víctor Jiménez-Jiménez
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Department of Health Science, Universidad Católica Santa Teresa de Jesús de Ávila, Ávila, Spain
| | - Daniel Jimenez-Carretero
- Cellomics Unit, Cell and Developmental Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Moreno Zamai
- Microscopy and Dynamic Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Cintia Folgueira
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas CIMUS, Santiago de Compostela, Spain
- Stress kinases in Diabetes, Cancer and Cardiovascular Disease lab. Cardiovascular risk factors & brain function program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Ana Cerezo
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Department of Molecular Pharmacology, Lilly Research Laboratories, Alcobendas, Spain
| | - Fidel-Nicolás Lolo
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Rubén Nogueiras
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas CIMUS, Santiago de Compostela, Spain
| | - Guadalupe Sabio
- Stress kinases in Diabetes, Cancer and Cardiovascular Disease lab. Cardiovascular risk factors & brain function program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Miguel Sánchez-Álvarez
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Cell Compartmentalization, Homeostasis and Inflammation lab, Department of Metabolic and Inflammatory Diseases. Instituto de Investigaciones Biomédicas "Sols-Morreale"-CSIC, Madrid, Spain
| | - Asier Echarri
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Mechanobiology of Organelles lab. Department of Cellular and Molecular Biology. Centro de Investigaciones Biológicas Margarita Salas - CSIC, Madrid, Spain
| | - Ricardo Garcia
- ForceTool group, Instituto de Ciencia de Materiales de Madrid (ICMM), CSIC, Madrid, Spain
| | - Miguel A Del Pozo
- Mechanoadaptation and Caveolae Biology lab, Novel mechanisms in atherosclerosis program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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6
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Yaikwawong M, Ek-Eudomsuk P, Sittithumcharee G, Anupunpisit V, Peerapatdit T, Deerochanawong C, Himathongkam T, Jirawatnotai S, Chuengsamarn S. A prevalent caveolin-1 gene rs926198 variant is associated with type 2 diabetes mellitus in the Thai population. Sci Rep 2024; 14:27616. [PMID: 39528503 PMCID: PMC11555279 DOI: 10.1038/s41598-024-78534-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
This study investigated the associations between CAV1 variants and metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and cardiometabolic risk factors, as well as the influence of CAV1 variants on CAV1 mRNA expression. We genotyped 743 T2DM patients for CAV1 variants. Multiple logistic regression was conducted to adjust for sex, age, and body mass index (BMI), and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. The expression of mRNA was measured by reverse transcription polymerase chain reaction. The rs926198 variant, but not the rs3807989 variant, was associated with T2DM. Crude ORs were 1.87 (95% CI: 1.32-2.69, p = 0.0005) and adjusted ORs were 1.81 (95% CI: 1.12-2.96, p = 0.016), respectively. Additionally, patients with Mets and T2DM who had the rs926198 variant exhibited a significant 44.3% reduction in CAV1 mRNA expression (P < 0.05). Clinical samples revealed that the rs926198 variant is strongly linked to T2DM, with significantly reduced CAV1 mRNA. Our findings suggest a crucial role for the rs926198 variant in T2DM, indicating its potential for prevention, diagnosis, and intervention purposes.
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Affiliation(s)
- Metha Yaikwawong
- Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Pornpimon Ek-Eudomsuk
- Siriraj Center of Research for Excellence, Siriraj Center of Research for Excellence for Systems Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Gunya Sittithumcharee
- Siriraj Center of Research for Excellence, Siriraj Center of Research for Excellence for Systems Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Vipavee Anupunpisit
- Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Bangkok, 10110, Thailand
| | - Thavatchai Peerapatdit
- Division of Endocrinology and Metabolism, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Chaicharn Deerochanawong
- Division of Endocrinology and Metabolism, Department of Medicine, Rajavithi Hospital, Bangkok, 10400, Thailand
| | | | - Siwanon Jirawatnotai
- Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
- Siriraj Center of Research for Excellence, Siriraj Center of Research for Excellence for Systems Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
- Faculty of Pharmacy, Silpakorn University, Mueang District, Nakhon Pathom, 73000, Thailand.
| | - Somlak Chuengsamarn
- Division of Endocrinology and Metabolism, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakhon Nayok, 26120, Thailand.
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7
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An Z, Tian J, Zhao X, Liu L, Yang X, Zhang M, Zhang L, Song X. Regulation of cardiovascular and cardiac functions by caveolins. FEBS J 2024; 291:3753-3761. [PMID: 37060249 DOI: 10.1111/febs.16798] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/06/2023] [Accepted: 04/13/2023] [Indexed: 04/16/2023]
Abstract
Caveolae are intracellular vesicles with diameters ranging from 50 to 100 nm. The role of caveolins in mediating oxidative stress, autophagy, apoptosis, fibrosis, and vascular remodeling has attracted increasing attention in cardiovascular therapy. Several studies have suggested that caveolin could be a therapeutic target for the treatment of cardiac and/or vascular injury via several pathophysiological mechanisms. Despite substantial advances in our understanding of the basic biology of vesicles over the past decade, the relevance and specific role of these mechanisms in cardiovascular homeostasis remains ambiguous. Here, we review the macroscopic role of caveolins in protecting cardiac function and, at the microscopic level, examine possible cardioprotective caveolar mechanisms, including their antioxidative stress, antiapoptosis, autophagy-regulatory, antifibrosis, and angiogenesis-promoting properties. We believe that the role of caveolins in cardiac functioning has not been fully elucidated and is an important line of future research with several cardioprotective implications.
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Affiliation(s)
- Ziyu An
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jinfan Tian
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Libo Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Department of Cardiology, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Xueyao Yang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Mingduo Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lijun Zhang
- Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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8
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Zhang Z, Yu Z, Liang D, Song K, Kong X, He M, Liao X, Huang Z, Kang A, Bai R, Ren Y. Roles of lipid droplets and related proteins in metabolic diseases. Lipids Health Dis 2024; 23:218. [PMID: 39030618 PMCID: PMC11264848 DOI: 10.1186/s12944-024-02212-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024] Open
Abstract
Lipid droplets (LDs), which are active organelles, derive from the monolayer membrane of the endoplasmic reticulum and encapsulate neutral lipids internally. LD-associated proteins like RAB, those in the PLIN family, and those in the CIDE family participate in LD formation and development, and they are active players in various diseases, organelles, and metabolic processes (i.e., obesity, non-alcoholic fatty liver disease, and autophagy). Our synthesis on existing research includes insights from the formation of LDs to their mechanisms of action, to provide an overview needed for advancing research into metabolic diseases and lipid metabolism.
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Affiliation(s)
- Zhongyang Zhang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Zhenghang Yu
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Dianyuan Liang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Ke Song
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Xiangxin Kong
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Ming He
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
| | - Xinxin Liao
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Ziyan Huang
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Aijia Kang
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Rubing Bai
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China.
| | - Yixing Ren
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China.
- General Surgery, Chengdu XinHua Hospital Affiliated to North Sichuan Medical College, Chengdu, 610000, China.
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9
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Zhang X, Tian L, Majumdar A, Scheller EL. Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations. Compr Physiol 2024; 14:5521-5579. [PMID: 39109972 PMCID: PMC11725182 DOI: 10.1002/cphy.c230016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Linda Tian
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Erica L. Scheller
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
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10
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Akinci G, Alyaarubi S, Patni N, Alhashmi N, Al-Shidhani A, Prodam F, Gagne N, Babalola F, Al Senani A, Muniraj K, Elsayed SM, Beghini M, Saydam BO, Allawati M, Vaishnav MS, Can E, Simsir IY, Sorkina E, Dursun F, Kamrath C, Cavdar U, Chakraborty PP, Dogan OA, Al Hosin A, Al Maimani A, Comunoglu N, Hamed A, Huseinbegovic T, Scherer T, Curtis J, Brown RJ, Topaloglu H, Simha V, Wabitsch M, Tuysuz B, Oral EA, Akinci B, Garg A. Metabolic and other morbid complications in congenital generalized lipodystrophy type 4. Am J Med Genet A 2024; 194:e63533. [PMID: 38234231 PMCID: PMC11060913 DOI: 10.1002/ajmg.a.63533] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/10/2023] [Accepted: 12/13/2023] [Indexed: 01/19/2024]
Abstract
Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.
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Affiliation(s)
- Gulcin Akinci
- Department of Pediatric Neurology, University of Health Sciences, Izmir Faculty of Medicine, Behcet Uz Children’s Hospital, Izmir, Turkey
| | | | - Nivedita Patni
- Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Nadia Alhashmi
- Clinical and Biochemical Genetics Department, Child Health Department, Royal Hospital, Muscat, Oman
| | | | - Flavia Prodam
- Division of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Nancy Gagne
- Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Funmbi Babalola
- The Hospital for Sick Children, Department of Pediatrics, Toronto, ON, Canada
| | - Aisha Al Senani
- National Diabetes and Endocrine Center, Royal Hospital, Muscat, Oman
| | - Kavitha Muniraj
- Samatvam Diabetes Endocrinology and Medical Center, Bangalore, India
| | - Solaf M. Elsayed
- Medical Genetics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marianna Beghini
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Austria
| | | | | | - Madhumati S Vaishnav
- Samatvam Diabetes Endocrinology and Medical Center, Bangalore, India
- Indian Institute of Science, Center for Nano Science and Engineering, Bangalore, India
| | - Ender Can
- Division of Pediatric Neurology, Gaziantep Children’s Hospital, Gaziantep, Turkey
| | | | - Ekaterina Sorkina
- Endocrinology Research Centre, Moscow, Russia
- Clinical Research Facility, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Fatma Dursun
- Department of Pediatric Endocrinology, Umraniye Training and Research Hospital, Istanbul, Turkey
| | - Clemens Kamrath
- Centre of Child and Adolescent Medicine, Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen, Germany
| | - Umit Cavdar
- Division of Endocrinology, Katip Celebi University, Izmir, Turkey
| | - Partha P. Chakraborty
- Department of Endocrinology and Metabolism, Medical College Hospital, Kolkata, India
| | - Ozlem Akgun Dogan
- Department of Pediatric Genetics, Acibadem Mehmet Ali Aydınlar University, Istanbul, Turkey
| | | | | | - Nil Comunoglu
- Department of Pathology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey
| | - Ahmed Hamed
- Child Health Department, Royal Hospital, Muscat, Oman
| | - Tea Huseinbegovic
- Division of Endocrinology, Department of Internal Medicine, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA
| | - Thomas Scherer
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Jacqueline Curtis
- The Hospital for Sick Children, Department of Pediatrics, Toronto, ON, Canada
| | - Rebecca J. Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Haluk Topaloglu
- Department of Pediatric Neurology, Yeditepe University, Istanbul, Turkey
| | - Vinaya Simha
- Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Center Ulm, Ulm, Germany
| | - Beyhan Tuysuz
- Department of Pediatric Genetics, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey
| | - Elif A. Oral
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Baris Akinci
- DEPARK, Dokuz Eylul University, Izmir, Turkey
- Izmir Biomedicine and Genome Center, Izmir, Turkey
| | - Abhimanyu Garg
- Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA
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11
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Amiri Khosroshahi R, Mirzababaei A, Setayesh L, Bagheri R, Heidari Seyedmahalleh M, Wong A, Suzuki K, Mirzaei K. Dietary Insulin Index (DII) and Dietary Insulin load (DIL) and Caveolin gene variant interaction on cardiometabolic risk factors among overweight and obese women: a cross-sectional study. Eur J Med Res 2024; 29:74. [PMID: 38268038 PMCID: PMC10807169 DOI: 10.1186/s40001-024-01638-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 01/03/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Studies have shown that Caveolin gene polymorphisms (CAV-1) are involved in chronic diseases, such as metabolic syndrome. Moreover, the dietary insulin index (DII) and dietary insulin load (DIL) have been shown to potentially elicit favorable effects on cardiovascular disease (CVD) risk. Therefore, this study sought to investigate the effect of DII DIL and CAV-1 interaction on CVD risk factors. METHODS This cross-sectional study consisted of 333 overweight and obese women aged 18-48 years. Dietary intakes, DII, and DIL were evaluated using the 147-item food frequency questionnaire (FFQ). Serum profiles were measured by standard protocols. The CAV-1 rs 3,807,992 and anthropometric data were measured by the PCR-RFLP method and bioelectrical impedance analysis (BIA), respectively. Participants were also divided into three groups based on DII, DIL score, and rs3807992 genotype. RESULTS This comparative cross-sectional study was conducted on 333 women classified as overweight or obese. Participants with A allele for the caveolin genotype and higher DII score showed significant interactions with high-density lipoprotein (HDL) (P for AA = 0.006 and P for AG = 0.019) and CRI-I (P for AA < 0.001 and P for AG = 0.024). In participants with AA genotype and greater DII score, interactions were observed in weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, CRI-II, fat-free mass (FFM), and skeletal muscle mass (SMM) (P < 0.079). Those with higher DIL scores and AA genotype had higher weight (P = 0.033), FFM (P = 0.022), and SMM (P = 0.024). In addition, DIL interactions for waist/hip ratio (WHR), waist circumference (WC), triglyceride (TG), CRI-I, and body fat mass (BFM) among individuals with AA genotype, while an HDL interaction was observed in individuals with AG and AA (P < 0.066). CONCLUSION The findings of the present study indicate that people who carry the caveolin rs3807992 (A) allele and have greater DII and DIL scores are at higher risk for several cardiovascular disease and metabolic syndrome biomarkers. These results highlight that diet, gene variants, and their interaction, should be considered in the risk evaluation of developing CVD.
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Affiliation(s)
- Reza Amiri Khosroshahi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Leila Setayesh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Bagheri
- Department of Exercise Physiology, University of Isfahan, Isfahan, Iran
| | - Mohammad Heidari Seyedmahalleh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Alexei Wong
- Department of Health and Human Performance, Marymount University, Arlington, USA
| | - Katsuhiko Suzuki
- Faculty of Sport Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa, 359-1192, Japan.
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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12
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Adeva-Andany MM, Domínguez-Montero A, Adeva-Contreras L, Fernández-Fernández C, Carneiro-Freire N, González-Lucán M. Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases. Curr Diabetes Rev 2024; 20:e160823219824. [PMID: 37587805 DOI: 10.2174/1573399820666230816111624] [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: 01/12/2023] [Revised: 04/28/2023] [Accepted: 05/31/2023] [Indexed: 08/18/2023]
Abstract
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Alberto Domínguez-Montero
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | | | - Carlos Fernández-Fernández
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Natalia Carneiro-Freire
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Manuel González-Lucán
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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13
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Tiwari M, Mcilroy GD. From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy. Diabet Med 2023; 40:e15214. [PMID: 37638531 DOI: 10.1111/dme.15214] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/19/2023] [Accepted: 08/22/2023] [Indexed: 08/29/2023]
Abstract
AIMS Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. METHODS Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. RESULTS A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground-breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting-edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. CONCLUSIONS Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.
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Affiliation(s)
- Mansi Tiwari
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
| | - George D Mcilroy
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
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14
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Neuhaus M, Fryklund C, Taylor H, Borreguero-Muñoz A, Kopietz F, Ardalani H, Rogova O, Stirrat L, Bremner SK, Spégel P, Bryant NJ, Gould GW, Stenkula KG. EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events. Mol Biol Cell 2023; 34:ar124. [PMID: 37703099 PMCID: PMC10846623 DOI: 10.1091/mbc.e23-03-0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/14/2023] Open
Abstract
Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.
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Affiliation(s)
- Mathis Neuhaus
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
| | - Claes Fryklund
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
| | - Holly Taylor
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | | | - Franziska Kopietz
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
| | - Hamidreza Ardalani
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, 22241 Lund, Sweden
| | - Oksana Rogova
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, 22241 Lund, Sweden
| | - Laura Stirrat
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | - Shaun K. Bremner
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | - Peter Spégel
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, 22241 Lund, Sweden
| | - Nia J. Bryant
- Department of Biology and York Biomedical Research Institute, University of York, York YO10 5DD, UK
| | - Gwyn W. Gould
- Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
| | - Karin G. Stenkula
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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15
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Hall TE, Ariotti N, Lo HP, Rae J, Ferguson C, Martel N, Lim YW, Giacomotto J, Parton RG. Cell surface plasticity in response to shape change in the whole organism. Curr Biol 2023; 33:4276-4284.e4. [PMID: 37729911 DOI: 10.1016/j.cub.2023.08.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/27/2023] [Accepted: 08/23/2023] [Indexed: 09/22/2023]
Abstract
Plasma membrane rupture can result in catastrophic cell death. The skeletal muscle fiber plasma membrane, the sarcolemma, provides an extreme example of a membrane subject to mechanical stress since these cells specifically evolved to generate contraction and movement. A quantitative model correlating ultrastructural remodeling of surface architecture with tissue changes in vivo is required to understand how membrane domains contribute to the shape changes associated with tissue deformation in whole animals. We and others have shown that loss of caveolae, small invaginations of the plasma membrane particularly prevalent in the muscle sarcolemma, renders the plasma membrane more susceptible to rupture during stretch.1,2,3 While it is thought that caveolae are able to flatten and be absorbed into the bulk membrane to buffer local membrane expansion, a direct demonstration of this model in vivo has been unachievable since it would require measurement of caveolae at the nanoscale combined with detailed whole-animal morphometrics under conditions of perturbation. Here, we describe the development and application of the "active trapping model" where embryonic zebrafish are immobilized in a curved state that mimics natural body axis curvature during an escape response. The model is amenable to multiscale, multimodal imaging including high-resolution whole-animal three-dimensional quantitative electron microscopy. Using the active trapping model, we demonstrate the essential role of caveolae in maintaining sarcolemmal integrity and quantify the specific contribution of caveolar-derived membrane to surface expansion. We show that caveolae directly contribute to an increase in plasma membrane surface area under physiologically relevant membrane deformation conditions.
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Affiliation(s)
- Thomas E Hall
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
| | - Nicholas Ariotti
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Harriet P Lo
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - James Rae
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Charles Ferguson
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Nick Martel
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Ye-Wheen Lim
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Jean Giacomotto
- Griffith Institute for Drug Discovery, Centre for Cellular Phenomics, School of Environment and Science, Griffith University, Brisbane, QLD 4111, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Robert G Parton
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, QLD 4072, Australia.
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16
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Adeva-Andany MM, Funcasta-Calderón R, Fernández-Fernández C, Ameneiros-Rodríguez E, Vila-Altesor M, Castro-Quintela E. The metabolic effects of APOL1 in humans. Pflugers Arch 2023:10.1007/s00424-023-02821-z. [PMID: 37261508 PMCID: PMC10233197 DOI: 10.1007/s00424-023-02821-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/04/2023] [Accepted: 05/21/2023] [Indexed: 06/02/2023]
Abstract
Harboring apolipoprotein L1 (APOL1) variants coded by the G1 or G2 alleles of the APOL1 gene increases the risk for collapsing glomerulopathy, focal segmental glomerulosclerosis, albuminuria, chronic kidney disease, and accelerated kidney function decline towards end-stage kidney disease. However, most subjects carrying APOL1 variants do not develop the kidney phenotype unless a second clinical condition adds to the genotype, indicating that modifying factors modulate the genotype-phenotype correlation. Subjects with an APOL1 high-risk genotype are more likely to develop essential hypertension or obesity, suggesting that carriers of APOL1 risk variants experience more pronounced insulin resistance compared to noncarriers. Likewise, arterionephrosclerosis (the pathological correlate of hypertension-associated nephropathy) and glomerulomegaly take place among carriers of APOL1 risk variants, and these pathological changes are also present in conditions associated with insulin resistance, such as essential hypertension, aging, and diabetes. Insulin resistance may contribute to the clinical features associated with the APOL1 high-risk genotype. Unlike carriers of wild-type APOL1, bearers of APOL1 variants show impaired formation of lipid droplets, which may contribute to inducing insulin resistance. Nascent lipid droplets normally detach from the endoplasmic reticulum into the cytoplasm, although the proteins that enable this process remain to be fully defined. Wild-type APOL1 is located in the lipid droplet, whereas mutated APOL1 remains sited at the endoplasmic reticulum, suggesting that normal APOL1 may participate in lipid droplet biogenesis. The defective formation of lipid droplets is associated with insulin resistance, which in turn may modulate the clinical phenotype present in carriers of APOL1 risk variants.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406, Ferrol, Spain.
| | - Raquel Funcasta-Calderón
- Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406, Ferrol, Spain
| | - Carlos Fernández-Fernández
- Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406, Ferrol, Spain
| | - Eva Ameneiros-Rodríguez
- Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406, Ferrol, Spain
| | - Matilde Vila-Altesor
- Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406, Ferrol, Spain
| | - Elvira Castro-Quintela
- Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406, Ferrol, Spain
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17
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Zadoorian A, Du X, Yang H. Lipid droplet biogenesis and functions in health and disease. Nat Rev Endocrinol 2023:10.1038/s41574-023-00845-0. [PMID: 37221402 DOI: 10.1038/s41574-023-00845-0] [Citation(s) in RCA: 208] [Impact Index Per Article: 104.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/25/2023] [Indexed: 05/25/2023]
Abstract
Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage. Advances uncovering the intricacies of their biogenesis and the diversity of their physiological and pathological roles have yielded new insights into lipid droplet biology. Despite these insights, the mechanisms governing the biogenesis and functions of lipid droplets remain incompletely understood. Moreover, the causal relationship between the biogenesis and function of lipid droplets and human diseases is poorly resolved. Here, we provide an update on the current understanding of the biogenesis and functions of lipid droplets in health and disease, highlighting a key role for lipid droplet biogenesis in alleviating cellular stresses. We also discuss therapeutic strategies of targeting lipid droplet biogenesis, growth or degradation that could be applied in the future to common diseases, such as cancer, hepatic steatosis and viral infection.
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Affiliation(s)
- Armella Zadoorian
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia
| | - Ximing Du
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia
| | - Hongyuan Yang
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
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18
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Li D, Miao J, Pan L, Zhou Y, Gao Z, Bi Y, Tang J. Integrated lipidomics and transcriptomics analysis reveal lipid metabolism disturbance in scallop (Chlamys farreri) exposure to benzo[a]pyrene. CHEMOSPHERE 2023; 331:138787. [PMID: 37119930 DOI: 10.1016/j.chemosphere.2023.138787] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
Benzo[a]pyrene (B[a]P) commonly bioaccumulates in lipid-rich tissues due to its lipophilicity and further affects lipid metabolism. The present study systematically investigated the lipid metabolism disturbance in digestive glands of scallops (Chlamys farreri) exposure to B[a]P, based on lipidomics, transcriptomics, molecular and biochemical analysis. We exposed the scallops to environmentally relevant concentrations of B[a]P for 21 days. The bioaccumulation of B[a]P, lipid content and lipid peroxidation in digestive glands were measured. Integrated lipidomics and transcriptomics analysis, the differential lipid species were identified and key genes based on the pathways in which genes and lipid species involved together were selected in scallop exposure to 10 μg/L B[a]P. The changes of lipid profile showed that triglycerides (TGs) were accumulated after 21 days exposure, while the phospholipids (PLs) decreased demonstrated membrane structures were disrupted by B[a]P. In combination with the change of gene expression, we speculated that B[a]P could induce lipids accumulation by up-regulating lipid synthesis-related genes expression, down-regulating lipolysis-related genes expression and interfering with lipid transport. Overall, this study provides new insights into the mechanisms of lipid metabolism disturbance in bivalves exposed to PAHs, and establishes a foundation for understanding the bioaccumulation mechanism of B[a]P in aquatic organisms, which is of great importance for further ecotoxicological study.
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Affiliation(s)
- Dongyu Li
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Jingjing Miao
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Luqing Pan
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China.
| | - Yueyao Zhou
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Zhongyuan Gao
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Yaqi Bi
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Jian Tang
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
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19
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Kenworthy AK. The building blocks of caveolae revealed: caveolins finally take center stage. Biochem Soc Trans 2023; 51:855-869. [PMID: 37082988 PMCID: PMC10212548 DOI: 10.1042/bst20221298] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/07/2023] [Accepted: 04/14/2023] [Indexed: 04/22/2023]
Abstract
The ability of cells to divide, migrate, relay signals, sense mechanical stimuli, and respond to stress all rely on nanoscale invaginations of the plasma membrane known as caveolae. The caveolins, a family of monotopic membrane proteins, form the inner layer of the caveolar coat. Caveolins have long been implicated in the generation of membrane curvature, in addition to serving as scaffolds for signaling proteins. Until recently, however, the molecular architecture of caveolins was unknown, making it impossible to understand how they operate at a mechanistic level. Over the past year, two independent lines of evidence - experimental and computational - have now converged to provide the first-ever glimpse into the structure of the oligomeric caveolin complexes that function as the building blocks of caveolae. Here, we summarize how these discoveries are transforming our understanding of this long-enigmatic protein family and their role in caveolae assembly and function. We present new models inspired by the structure for how caveolins oligomerize, remodel membranes, interact with their binding partners, and reorganize when mutated. Finally, we discuss emerging insights into structural differences among caveolin family members that enable them to support the proper functions of diverse tissues and organisms.
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Affiliation(s)
- Anne K. Kenworthy
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, U.S.A
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, U.S.A
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20
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Han B, Gulsevin A, Connolly S, Wang T, Meyer B, Porta J, Tiwari A, Deng A, Chang L, Peskova Y, Mchaourab HS, Karakas E, Ohi MD, Meiler J, Kenworthy AK. Structural analysis of the P132L disease mutation in caveolin-1 reveals its role in the assembly of oligomeric complexes. J Biol Chem 2023; 299:104574. [PMID: 36870682 PMCID: PMC10124911 DOI: 10.1016/j.jbc.2023.104574] [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: 05/25/2022] [Revised: 01/09/2023] [Accepted: 02/03/2023] [Indexed: 03/06/2023] Open
Abstract
Caveolin-1 (CAV1) is a membrane-sculpting protein that oligomerizes to generate flask-shaped invaginations of the plasma membrane known as caveolae. Mutations in CAV1 have been linked to multiple diseases in humans. Such mutations often interfere with oligomerization and the intracellular trafficking processes required for successful caveolae assembly, but the molecular mechanisms underlying these defects have not been structurally explained. Here, we investigate how a disease-associated mutation in one of the most highly conserved residues in CAV1, P132L, affects CAV1 structure and oligomerization. We show that P132 is positioned at a major site of protomer-protomer interactions within the CAV1 complex, providing a structural explanation for why the mutant protein fails to homo-oligomerize correctly. Using a combination of computational, structural, biochemical, and cell biological approaches, we find that despite its homo-oligomerization defects P132L is capable of forming mixed hetero-oligomeric complexes with WT CAV1 and that these complexes can be incorporated into caveolae. These findings provide insights into the fundamental mechanisms that control the formation of homo- and hetero-oligomers of caveolins that are essential for caveolae biogenesis, as well as how these processes are disrupted in human disease.
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Affiliation(s)
- Bing Han
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Alican Gulsevin
- Department of Chemistry, Vanderbilt University, Nashville, TN, USA
| | - Sarah Connolly
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Ting Wang
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Brigitte Meyer
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Jason Porta
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Ajit Tiwari
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Angie Deng
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Louise Chang
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Yelena Peskova
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Hassane S Mchaourab
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Erkan Karakas
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Melanie D Ohi
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Jens Meiler
- Department of Chemistry, Vanderbilt University, Nashville, TN, USA; Institute for Drug Discovery, Leipzig University, Leipzig, Germany
| | - Anne K Kenworthy
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA.
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21
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Sotodosos-Alonso L, Pulgarín-Alfaro M, Del Pozo MA. Caveolae Mechanotransduction at the Interface between Cytoskeleton and Extracellular Matrix. Cells 2023; 12:cells12060942. [PMID: 36980283 PMCID: PMC10047380 DOI: 10.3390/cells12060942] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
The plasma membrane (PM) is subjected to multiple mechanical forces, and it must adapt and respond to them. PM invaginations named caveolae, with a specific protein and lipid composition, play a crucial role in this mechanosensing and mechanotransduction process. They respond to PM tension changes by flattening, contributing to the buffering of high-range increases in mechanical tension, while novel structures termed dolines, sharing Caveolin1 as the main component, gradually respond to low and medium forces. Caveolae are associated with different types of cytoskeletal filaments, which regulate membrane tension and also initiate multiple mechanotransduction pathways. Caveolar components sense the mechanical properties of the substrate and orchestrate responses that modify the extracellular matrix (ECM) according to these stimuli. They perform this function through both physical remodeling of ECM, where the actin cytoskeleton is a central player, and via the chemical alteration of the ECM composition by exosome deposition. Here, we review mechanotransduction regulation mediated by caveolae and caveolar components, focusing on how mechanical cues are transmitted through the cellular cytoskeleton and how caveolae respond and remodel the ECM.
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Affiliation(s)
- Laura Sotodosos-Alonso
- Mechanoadaptation and Caveolae Biology Laboratory, Novel Mechanisms of Atherosclerosis Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Marta Pulgarín-Alfaro
- Mechanoadaptation and Caveolae Biology Laboratory, Novel Mechanisms of Atherosclerosis Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Miguel A Del Pozo
- Mechanoadaptation and Caveolae Biology Laboratory, Novel Mechanisms of Atherosclerosis Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
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22
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Abstract
The global prevalences of obesity and type 2 diabetes mellitus have reached epidemic status, presenting a heavy burden on society. It is therefore essential to find novel mechanisms and targets that could be utilized in potential treatment strategies and, as such, intracellular membrane trafficking has re-emerged as a regulatory tool for controlling metabolic homeostasis. Membrane trafficking is an essential physiological process that is responsible for the sorting and distribution of signalling receptors, membrane transporters and hormones or other ligands between different intracellular compartments and the plasma membrane. Dysregulation of intracellular transport is associated with many human diseases, including cancer, neurodegeneration, immune deficiencies and metabolic diseases, such as type 2 diabetes mellitus and its associated complications. This Review focuses on the latest advances on the role of endosomal membrane trafficking in metabolic physiology and pathology in vivo, highlighting the importance of this research field in targeting metabolic diseases.
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Affiliation(s)
- Jerome Gilleron
- Université Côte d'Azur, Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1065 C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France.
| | - Anja Zeigerer
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
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23
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Aboy-Pardal MC, Jimenez-Carretero D, Terrés-Domínguez S, Pavón DM, Sotodosos-Alonso L, Jiménez-Jiménez V, Sánchez-Cabo F, Del Pozo MA. A deep learning-based tool for the automated detection and analysis of caveolae in transmission electron microscopy images. Comput Struct Biotechnol J 2022; 21:224-237. [PMID: 36544477 PMCID: PMC9755247 DOI: 10.1016/j.csbj.2022.11.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/29/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Caveolae are nanoscopic and mechanosensitive invaginations of the plasma membrane, essential for adipocyte biology. Transmission electron microscopy (TEM) offers the highest resolution for caveolae visualization, but provides complicated images that are difficult to classify or segment using traditional automated algorithms such as threshold-based methods. As a result, the time-consuming tasks of localization and quantification of caveolae are currently performed manually. We used the Keras library in R to train a convolutional neural network with a total of 36,000 TEM image crops obtained from adipocytes previously annotated manually by an expert. The resulting model can differentiate caveolae from non-caveolae regions with a 97.44% accuracy. The predictions of this model are further processed to obtain caveolae central coordinate detection and cytoplasm boundary delimitation. The model correctly finds negligible caveolae predictions in images from caveolae depleted Cav1-/- adipocytes. In large reconstructions of adipocyte sections, model and human performances are comparable. We thus provide a new tool for accurate caveolae automated analysis that could speed up and assist in the characterization of the cellular mechanical response.
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Affiliation(s)
- María C.M. Aboy-Pardal
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Daniel Jimenez-Carretero
- Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares
(CNIC), 28029 Madrid, Spain
| | - Sara Terrés-Domínguez
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Dácil M. Pavón
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Laura Sotodosos-Alonso
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Víctor Jiménez-Jiménez
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
| | - Fátima Sánchez-Cabo
- Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares
(CNIC), 28029 Madrid, Spain
| | - Miguel A. Del Pozo
- Mechanoadaptation and Caveolae Biology lab, Cell and Developmental
Biology Area. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029
Madrid, Spain
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24
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Crewe C, Chen S, Bu D, Gliniak CM, Wernstedt Asterholm I, Yu XX, Joffin N, de Souza CO, Funcke JB, Oh DY, Varlamov O, Robino JJ, Gordillo R, Scherer PE. Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-Independent Glucose Uptake via Extracellular Vesicles. Diabetes 2022; 71:2496-2512. [PMID: 35880782 PMCID: PMC9750943 DOI: 10.2337/db22-0035] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 07/20/2022] [Indexed: 01/11/2023]
Abstract
Caveolin-1 (cav1) is an important structural and signaling component of plasma membrane invaginations called caveolae and is abundant in adipocytes. As previously reported, adipocyte-specific ablation of the cav1 gene (ad-cav1 knockout [KO] mouse) does not result in elimination of the protein, as cav1 protein traffics to adipocytes from neighboring endothelial cells. However, this mouse is a functional KO because adipocyte caveolar structures are depleted. Compared with controls, ad-cav1KO mice on a high-fat diet (HFD) display improved whole-body glucose clearance despite complete loss of glucose-stimulated insulin secretion, blunted insulin-stimulated AKT activation in metabolic tissues, and partial lipodystrophy. The cause is increased insulin-independent glucose uptake by white adipose tissue (AT) and reduced hepatic gluconeogenesis. Furthermore, HFD-fed ad-cav1KO mice display significant AT inflammation, fibrosis, mitochondrial dysfunction, and dysregulated lipid metabolism. The glucose clearance phenotype of the ad-cav1KO mice is at least partially mediated by AT small extracellular vesicles (AT-sEVs). Injection of control mice with AT-sEVs from ad-cav1KO mice phenocopies ad-cav1KO characteristics. Interestingly, AT-sEVs from ad-cav1KO mice propagate the phenotype of the AT to the liver. These data indicate that ad-cav1 is essential for healthy adaptation of the AT to overnutrition and prevents aberrant propagation of negative phenotypes to other organs by EVs.
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Affiliation(s)
- Clair Crewe
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO
- Division of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Shiuhwei Chen
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Dawei Bu
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Christy M. Gliniak
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Ingrid Wernstedt Asterholm
- Department of Physiology (Metabolic Physiology Research Unit), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Xin Xin Yu
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Nolwenn Joffin
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Camila O. de Souza
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Jan-Bernd Funcke
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Da Young Oh
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Oleg Varlamov
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Jacob J. Robino
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR
| | - Ruth Gordillo
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Philipp E. Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX
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25
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Dugail I, Le Lay S. Adipocyte-Derived Extracellular Vesicles: Caveolin Matters. Diabetes 2022; 71:2477-2479. [PMID: 36409791 PMCID: PMC9862523 DOI: 10.2337/dbi22-0032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/02/2022] [Indexed: 11/22/2022]
Affiliation(s)
| | - Soazig Le Lay
- Université de Nantes, CNRS, INSERM, l’Institut du Thorax, Nantes, France
- Université D’Angers, SFR ICAT, Angers, France
- Corresponding author: Soazig Le Lay,
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26
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Abstract
PURPOSE OF REVIEW Genetic or acquired lipodystrophies are characterized by selective loss of body fat along with predisposition towards metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovarian syndrome, and acanthosis nigricans. In this review, we discuss the various subtypes and when to suspect and how to diagnose lipodystrophy. RECENT FINDINGS The four major subtypes are autosomal recessive, congenital generalized lipodystrophy (CGL); acquired generalized lipodystrophy (AGL), mostly an autoimmune disorder; autosomal dominant or recessive familial partial lipodystrophy (FPLD); and acquired partial lipodystrophy (APL), an autoimmune disorder. Diagnosis of lipodystrophy is mainly based upon physical examination findings of loss of body fat and can be supported by body composition analysis by skinfold measurements, dual-energy x-ray absorptiometry, and whole-body magnetic resonance imaging. Confirmatory genetic testing is helpful in the proband and at-risk family members with suspected genetic lipodystrophies. The treatment is directed towards the specific comorbidities and metabolic complications, and there is no treatment to reverse body fat loss. Metreleptin should be considered as the first-line therapy for metabolic complications in patients with generalized lipodystrophy and for prevention of comorbidities in children. Metformin and insulin therapy are the best options for treating hyperglycemia and fibrates and/or fish oil for hypertriglyceridemia. Lipodystrophy should be suspected in lean and muscular subjects presenting with diabetes mellitus, hypertriglyceridemia, non-alcoholic fatty liver disease, polycystic ovarian syndrome, or amenorrhea. Diabetologists should be aware of lipodystrophies and consider genetic varieties as an important subtype of monogenic diabetes.
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Affiliation(s)
- Nivedita Patni
- Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Abhimanyu Garg
- Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8537, USA.
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27
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Lecoutre S, Lambert M, Drygalski K, Dugail I, Maqdasy S, Hautefeuille M, Clément K. Importance of the Microenvironment and Mechanosensing in Adipose Tissue Biology. Cells 2022; 11:cells11152310. [PMID: 35954152 PMCID: PMC9367348 DOI: 10.3390/cells11152310] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/19/2022] [Accepted: 07/23/2022] [Indexed: 11/16/2022] Open
Abstract
The expansion of adipose tissue is an adaptive mechanism that increases nutrient buffering capacity in response to an overall positive energy balance. Over the course of expansion, the adipose microenvironment undergoes continual remodeling to maintain its structural and functional integrity. However, in the long run, adipose tissue remodeling, typically characterized by adipocyte hypertrophy, immune cells infiltration, fibrosis and changes in vascular architecture, generates mechanical stress on adipose cells. This mechanical stimulus is then transduced into a biochemical signal that alters adipose function through mechanotransduction. In this review, we describe the physical changes occurring during adipose tissue remodeling, and how they regulate adipose cell physiology and promote obesity-associated dysfunction in adipose tissue.
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Affiliation(s)
- Simon Lecoutre
- Nutrition and Obesities: Systemic Approaches Research Group (Nutri-Omics), Sorbonne Université, INSERM, F-75013 Paris, France; (S.L.); (K.D.); (I.D.)
| | - Mélanie Lambert
- Labex Inflamex, Université Sorbonne Paris Nord, INSERM, F-93000 Bobigny, France;
| | - Krzysztof Drygalski
- Nutrition and Obesities: Systemic Approaches Research Group (Nutri-Omics), Sorbonne Université, INSERM, F-75013 Paris, France; (S.L.); (K.D.); (I.D.)
| | - Isabelle Dugail
- Nutrition and Obesities: Systemic Approaches Research Group (Nutri-Omics), Sorbonne Université, INSERM, F-75013 Paris, France; (S.L.); (K.D.); (I.D.)
| | - Salwan Maqdasy
- Department of Medicine (H7), Karolinska Institutet Hospital, C2-94, 14186 Stockholm, Sweden;
| | - Mathieu Hautefeuille
- Laboratoire de Biologie du Développement (UMR 7622), IBPS, Sorbonne Université, F-75005 Paris, France;
| | - Karine Clément
- Nutrition and Obesities: Systemic Approaches Research Group (Nutri-Omics), Sorbonne Université, INSERM, F-75013 Paris, France; (S.L.); (K.D.); (I.D.)
- Assistance Publique Hôpitaux de Paris, Nutrition Department, CRNH Ile-de-France, Pitié-Salpêtrière Hospital, F-75013 Paris, France
- Correspondence: or
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28
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Porta JC, Han B, Gulsevin A, Chung JM, Peskova Y, Connolly S, Mchaourab HS, Meiler J, Karakas E, Kenworthy AK, Ohi MD. Molecular architecture of the human caveolin-1 complex. SCIENCE ADVANCES 2022; 8:eabn7232. [PMID: 35544577 PMCID: PMC9094659 DOI: 10.1126/sciadv.abn7232] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Membrane-sculpting proteins shape the morphology of cell membranes and facilitate remodeling in response to physiological and environmental cues. Complexes of the monotopic membrane protein caveolin function as essential curvature-generating components of caveolae, flask-shaped invaginations that sense and respond to plasma membrane tension. However, the structural basis for caveolin's membrane remodeling activity is currently unknown. Here, we show that, using cryo-electron microscopy, the human caveolin-1 complex is composed of 11 protomers organized into a tightly packed disc with a flat membrane-embedded surface. The structural insights suggest a previously unrecognized mechanism for how membrane-sculpting proteins interact with membranes and reveal how key regions of caveolin-1, including its scaffolding, oligomerization, and intramembrane domains, contribute to its function.
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Affiliation(s)
- Jason C. Porta
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Bing Han
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Alican Gulsevin
- Department of Chemistry, Vanderbilt University Nashville, TN, USA
| | - Jeong Min Chung
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Biotechnology, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Yelena Peskova
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Sarah Connolly
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Hassane S. Mchaourab
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Jens Meiler
- Department of Chemistry, Vanderbilt University Nashville, TN, USA
- Institute for Drug Discovery, Leipzig University, Germany
| | - Erkan Karakas
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Corresponding author. (E.K.); (A.K.K.); (M.D.O.)
| | - Anne K. Kenworthy
- Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA
- Corresponding author. (E.K.); (A.K.K.); (M.D.O.)
| | - Melanie D. Ohi
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA
- Corresponding author. (E.K.); (A.K.K.); (M.D.O.)
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Iqbal J, Jiang HL, Wu HX, Li L, Zhou YH, Hu N, Xiao F, Wang T, Xu SN, Zhou HD. Hereditary severe insulin resistance syndrome: Pathogenesis, pathophysiology, and clinical management. Genes Dis 2022. [PMID: 37492723 PMCID: PMC10363564 DOI: 10.1016/j.gendis.2022.03.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Severe insulin resistance has been linked to some of the most globally prevalent disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovarian syndrome, and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex syndromes, and obesity-related H-SIRS. Genes such as INSR, AKT2, TBC1D4, AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG, PLIN1, CIDEC, LIPE, PCYT1A, MC4R, LEP, POMC, SH2B1, RECQL2, RECQL3, ALMS1, PCNT, ZMPSTE24, PIK3R1, and POLD1 have been linked to H-SIRS. Its clinical features include insulin resistance, hyperglycemia, hyperandrogenism, severe dyslipidemia, fatty liver, abnormal topography of adipose tissue, and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy, insulin sensitization, exogenous insulin therapy, and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS, its highly variable clinical presentation, refusal to be tested for genetic mutations by patients' family members who are not severely sick, unavailability of genetic testing, and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition, which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended, and long-term studies are required for genotype-phenotype differentiation and formulation of diagnostic and treatment protocols.
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Magré J, Prieur X. Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease. Int J Mol Sci 2022; 23:740. [PMID: 35054926 PMCID: PMC8775404 DOI: 10.3390/ijms23020740] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 02/05/2023] Open
Abstract
Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.
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Affiliation(s)
| | - Xavier Prieur
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, L’institut du Thorax, Université de Nantes, F-44000 Nantes, France;
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Le Lay S, Magré J, Prieur X. Not Enough Fat: Mouse Models of Inherited Lipodystrophy. Front Endocrinol (Lausanne) 2022; 13:785819. [PMID: 35250856 PMCID: PMC8895270 DOI: 10.3389/fendo.2022.785819] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/17/2022] [Indexed: 12/19/2022] Open
Abstract
Lipodystrophies belong to the heterogenous group of syndromes in which the primary defect is a generalized or partial absence of adipose tissue, which may be congenital or acquired in origin. Lipodystrophy should be considered in patients manifesting the combination of insulin resistance (with or without overt diabetes), dyslipidemia and fatty liver. Lipodystrophies are classified according to the etiology of the disease (genetic or acquired) and to the anatomical distribution of adipose tissue (generalized or partial). The mechanism of adipose tissue loss is specific to each syndrome, depending on the biological function of the mutated gene. Mice models, together with cellular studies have permitted clarification of the mechanisms by which human mutations deeply compromise adipocyte homeostasis. In addition, rodent models have proven to be crucial in deciphering the cardiometabolic consequences of the lack of adipose tissue such as NAFLD, muscle insulin resistance and cardiomyopathy. More precisely, tissue-specific transgenic and knockout mice have brought new tools to distinguish phenotypic traits that are the consequences of lipodystrophy from those that are cell-autonomous. In this review, we discuss the mice models of lipodystrophy including those of inherited human syndromes of generalized and partial lipodystrophy. We present how these models have demonstrated the central role of white adipose tissue in energetic homeostasis in general, including insulin sensitivity and lipid handling in particular. We underscore the differences reported with the human phenotype and discuss the limit of rodent models in recapitulating adipose tissue primary default. Finally, we present how these mice models have highlighted the function of the causative-genes and brought new insights into the pathophysiology of the cardiometabolic complications associated with lipodystrophy.
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Affiliation(s)
- Soazig Le Lay
- Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France
- Univ Angers, SFR ICAT, Angers, France
| | - Jocelyne Magré
- Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France
| | - Xavier Prieur
- Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France
- *Correspondence: Xavier Prieur,
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Campos JTADM, Oliveira MSD, Soares LP, Medeiros KAD, Campos LRDS, Lima JG. DNA repair-related genes and adipogenesis: Lessons from congenital lipodystrophies. Genet Mol Biol 2022; 45:e20220086. [DOI: 10.1590/1678-4685-gmb-2022-0086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 09/20/2022] [Indexed: 11/09/2022] Open
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Higuchi Y, Ogata T, Nakanishi N, Nishi M, Sakamoto A, Tsuji Y, Tomita S, Matoba S. Requirement of Cavin-2 for the expression and stability of IRβ in adequate adipocyte differentiation. Mol Metab 2021; 55:101416. [PMID: 34896640 PMCID: PMC8728525 DOI: 10.1016/j.molmet.2021.101416] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/29/2021] [Accepted: 12/07/2021] [Indexed: 12/22/2022] Open
Abstract
Objective Adipogenesis plays an essential role in maintaining energy and hormonal balance. Cavin-2, one of the caveolae-related proteins, is abundant in adipocytes, the leading site of adipogenesis. However, the details of the roles of Cavin-2 in adipogenesis remain unknown. Here, we demonstrate the requirement of Cavin-2 for the expression and stability of IRβ in adequate adipocyte differentiation. Methods Cavin-2 knockout (Cavin-2 KO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 8 weeks. We evaluated body weight, food intake, and several tissues. Glucose homeostasis was assessed by glucose and insulin tolerance tests. Insulin signaling in epididymal white adipose tissue (eWAT) was determined by Akt phosphorylation. In vitro study, we evaluated adipocyte differentiation, adipogenesis-related genes, and insulin signaling to clarify the relationship between Cavin-2 and adipogenesis under the manipulation of Cavin-2 expression. Results Caveolae structure decreased in eWAT of Cavin-2 KO mice and Cavin-2 knockdown 3T3-L1 cells. Cavin-2 enhanced the stability of insulin receptor (IR) through direct association at the plasma membrane in adipocytes, resulting in accelerated insulin/IR/Akt signaling-induced adipogenic gene expression in insulin-containing solution-stimulated 3T3-L1 adipocytes. IR-mediated Akt activation also enhanced Cavin-2 and IR expression. Cavin-2 knockout mice showed insulin resistance with dyslipidemia and pathological hypertrophic adipocytes after a HFD. Conclusions Cavin-2 enhances IR stability through binding IR and regulates insulin signaling, promoting adequate adipocyte differentiation. Our findings highlight the pivotal role of Cavin-2 in adipogenesis and lipid metabolism, which may help to develop novel therapies for pathological obesity and adipogenic disorders.
Cavin-2 expression is increased progressively during adipocyte differentiation. Cavin-2 knockout shows little caveolae in 3T3L-1 adipocytes and eWAT of mice. Cavin-2 positively regulates adipogenesis through IR stabilization. Cavin-2 knockout mice with a high-fat diet show insulin resistance and dyslipidemia.
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Affiliation(s)
- Yusuke Higuchi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takehiro Ogata
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; Department of Pathology and Cell Regulation, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Naohiko Nakanishi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Masahiro Nishi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Akira Sakamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yumika Tsuji
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shinya Tomita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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van Heerwaarde AA, Klomberg RCW, van Ravenswaaij-Arts CMA, Ploos van Amstel HK, Toekoen A, Jessurun F, Garg A, van der Kaay DCM. Approach to Diagnosing a Pediatric Patient With Severe Insulin Resistance in Low- or Middle-income Countries. J Clin Endocrinol Metab 2021; 106:3621-3633. [PMID: 34318892 PMCID: PMC8864731 DOI: 10.1210/clinem/dgab549] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Indexed: 11/19/2022]
Abstract
Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli-Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and, therefore, our approach is especially applicable to low- or middle-income countries.
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Affiliation(s)
- Alise A van Heerwaarde
- Department of Pediatrics, Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
| | - Renz C W Klomberg
- Department of Pediatrics, Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
| | - Conny M A van Ravenswaaij-Arts
- Department of Pediatrics, Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Aartie Toekoen
- Department of Pediatrics, Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
| | - Fariza Jessurun
- Department of Pediatrics, Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Abhimanyu Garg
- Division of Nutrition, and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA
- Dr. Abhimanyu Garg, UT Southwestern Medical Center, Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, Dallas, TX 75390, USA.
| | - Daniëlle C M van der Kaay
- Department of Pediatric Endocrinology, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, The Netherlands
- Correspondence: Dr. Daniëlle C. M. van der Kaay, Erasmus Medical Center – Sophia Children’s Hospital, Department of Pediatrics; PO 2060; 3000 CB Rotterdam, The Netherlands.
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Huang YH, Su TC, Wang CH, Wong SL, Chien YH, Wang YT, Hwu WL, Lee NC. RNA-seq of peripheral blood mononuclear cells of congenital generalized lipodystrophy type 2 patients. Sci Data 2021; 8:265. [PMID: 34645804 PMCID: PMC8514467 DOI: 10.1038/s41597-021-01040-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 08/26/2021] [Indexed: 12/03/2022] Open
Abstract
Illumina RNA-seq analysis was used to characterize the whole transcriptomes of peripheral blood mononuclear cells (PBMCs) from patients with congenital generalized lipodystrophy. RNA-seq information for seven patients with type 2 congenital generalized lipodystrophy (CGL2; Berardinelli-Seip congenital lipodystrophy, BSCL2) was obtained and compared with similar information for seven age- and sex-matched healthy control subjects. All seven CGL2 patients carried biallelic pathogenic mutations affecting the BSCL2 gene and had clinical symptoms of varying severity. The findings provide the whole-transcriptome signatures of PBMCs of CGL2 patients, allowing further exploration of gene expression patterns/signatures associated with the various clinical symptoms of patients with this disease.
| Measurement(s) | RNA-Seq • RNA | | Technology Type(s) | Illumina HiSeq. 2500 • RNA sequencing | | Sample Characteristic - Organism | Homo sapiens |
Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.15022521
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Affiliation(s)
- Yen-Hua Huang
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.,Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
| | - Tzu-Chien Su
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
| | - Chung-Hsing Wang
- Department of Pediatrics, Children's Hospital, China Medical University, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Siew-Lee Wong
- Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Yin-Hsiu Chien
- Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Tai Wang
- National Center for High-performance Computing, National Applied Research Laboratories, Hsinchu, Taiwan
| | - Wuh-Liang Hwu
- Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
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Fryklund C, Morén B, Shah S, Grossi M, Degerman E, Matthaeus C, Stenkula KG. EH Domain-Containing 2 Deficiency Restricts Adipose Tissue Expansion and Impairs Lipolysis in Primary Inguinal Adipocytes. Front Physiol 2021; 12:740666. [PMID: 34630160 PMCID: PMC8497890 DOI: 10.3389/fphys.2021.740666] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/25/2021] [Indexed: 11/21/2022] Open
Abstract
Lipid uptake can be facilitated via caveolae, specific plasma membrane invaginations abundantly expressed in adipocytes. The dynamin-related protein EH domain-containing 2 (EHD2) stabilizes caveolae at the cell surface. Here, we have examined the importance of EHD2 for lipid handling using primary adipocytes isolated from EHD2 knockout (Ehd2−/−) C57BL6/N mice. Following high-fat diet (HFD) feeding, we found a clear impairment of epididymal, but not inguinal, adipose tissue expansion in Ehd2−/− compared with Ehd2+/+ (WT) mice. Cell size distribution analysis revealed that Ehd2−/− mice had a lower proportion of small adipocytes, and an accumulation of medium-sized adipocytes in both epididymal and inguinal adipose tissue. Further, PPARγ activity, FABP4 and caveolin-1 expression were decreased in adipocytes isolated from Ehd2−/− mice. Inguinal adipocytes isolated from Ehd2−/− mice displayed reduced lipolysis in response to beta adrenergic receptor agonist, which was associated with reduced phosphorylation of perilipin-1 and hormone sensitive lipase (HSL). This impairment could not be rescued using a cAMP analog, indicating that impaired lipolysis in Ehd2−/− primary adipocytes likely occurs at the level of, or downstream of, protein kinase A (PKA). Altogether, these findings pinpoint the importance of EHD2 for maintained intracellular lipid metabolism, and emphasize differences in mechanisms regulating lipid handling in various adipose-tissue depots.
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Affiliation(s)
- Claes Fryklund
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Björn Morén
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Shrenika Shah
- School of Biomedical, Nutritional and Sport Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Mario Grossi
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Eva Degerman
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Claudia Matthaeus
- National Heart, Lung and Blood Institute, NIH, Bethesda, MD, United States
| | - Karin G Stenkula
- Department of Experimental Medical Science, Lund University, Lund, Sweden
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Tanaka T, Kusakabe T, Ebihara K, Aizawa-Abe M, Aotani D, Yorifuji T, Satoh M, Ogawa Y, Nakao K. Practice guideline for lipodystrophy syndromes-clinically important diseases of the Japan Endocrine Society (JES). Endocr J 2021; 68:1027-1042. [PMID: 34373417 DOI: 10.1507/endocrj.ej21-0110] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Affiliation(s)
- Tomohiro Tanaka
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya 467-8601, Japan
| | - Toru Kusakabe
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
- National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan
| | - Ken Ebihara
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi 329-0431, Japan
| | - Megumi Aizawa-Abe
- Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
| | - Daisuke Aotani
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya 467-8601, Japan
| | - Tohru Yorifuji
- Pediatric Endocrinology and Metabolism, Osaka City General Hospital, Osaka 534-0021, Japan
| | - Mari Satoh
- Pediatrics Center, Toho University Omori Medical Center, Tokyo 143-8540, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 821-8582, Japan
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kazuwa Nakao
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
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Jéru I. Genetics of lipodystrophy syndromes. Presse Med 2021; 50:104074. [PMID: 34562561 DOI: 10.1016/j.lpm.2021.104074] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/24/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022] Open
Abstract
Lipodystrophic syndromes (LS) constitute a clinically and genetically heterogeneous group of diseases characterized by a loss of adipose tissue. These syndromes are usually associated with metabolic complications, which are determinant for morbidity and mortality. The classical forms of LS include partial, generalized, and progeroid lipodystrophies. They are usually due to defects in proteins playing a key role in adipogenesis and adipocyte functions. More recently, systemic disorders combining lipodystrophy and multiple organ dysfunction have been described, including autoinflammatory syndromes, mitochondrial disorders, as well as other complex entities. To date, more than thirty genes have been implicated in the monogenic forms of LS, but the majority of them remain genetically-unexplained. The associated pathophysiological mechanisms also remain to be clarified in many instances. Next generation sequencing-based approaches allow simultaneous testing of multiple genes and have become crucial to speed up the identification of new disease-causing genes. The challenge for geneticists is now the interpretation of the amount of available genetic data, generated especially by exome and whole-genome sequencing. International recommendations on the interpretation and classification of variants have been set up and are regularly reassessed. Very close collaboration between geneticists, clinicians, and researchers will be necessary to make rapid progress in understanding the molecular and cellular basis of these diseases, and to promote personalized medicine.
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Affiliation(s)
- Isabelle Jéru
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris 75012, France.
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Generalized lipoatrophy syndromes. Presse Med 2021; 50:104075. [PMID: 34562560 DOI: 10.1016/j.lpm.2021.104075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/31/2021] [Accepted: 09/15/2021] [Indexed: 11/23/2022] Open
Abstract
Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe - as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.
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40
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Khatibi N, Mirzababaei A, Shiraseb F, Abaj F, Koohdani F, Mirzaei K. Interactions between caveolin 1 polymorphism and the Mediterranean and Mediterranean-DASH Intervention for Neurodegenerative Delay diet (MIND) diet on metabolic dyslipidemia in overweight and obese adult women: a cross-sectional study. BMC Res Notes 2021; 14:364. [PMID: 34544501 PMCID: PMC8454002 DOI: 10.1186/s13104-021-05777-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 09/07/2021] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The increased prevalence of metabolic dyslipidemia (MD) and its association with a variety of disorders raised a lot of attention to its management. Caveolin 1 (CAV1) the key protein in the caval structure of plasma membranes is many cell types that play an important role in its function. (CAV1) is a known gene associated with obesity. Today, a novel diet recognized as the Mediterranean and Mediterranean-DASH Intervention for Neurodegenerative Delay diet (MIND) is reported to have a positive effect on overall health. Hence, we aimed to investigate the interactions between CAV1 polymorphism and MIND diet on the MD in overweight and obese patients. RESULTS Remarkably, there was a significant interaction between the MIND diet and CAV1 rs3807992 for dyslipidemia (β = - 0.25 ± 132, P = 0.05) in the crude model. Whereby, subjects with dominant alleles had a lower risk of dyslipidemia and risk allele carriers with higher adherence to the MIND diet may exhibit the lower dyslipidemia. This study presented the CAV1 gene as a possible genetic marker in recognizing people at higher risks for metabolic diseases. It also indicated that using the MIND diet may help in improving dyslipidemia through providing a probable interaction with CAV1 rs3807992 polymorphism.
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Affiliation(s)
- Nasim Khatibi
- Shahid Sadoughi University of Medical Science, Yazd, Iran
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Farideh Shiraseb
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Fariba Koohdani
- Department of Cellular, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Molecular Nutrition, Tehran, Iran
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran.
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Shi D, Motamed M, Mejía-Benítez A, Li L, Lin E, Budhram D, Kaur Y, Meyre D. Genetic syndromes with diabetes: A systematic review. Obes Rev 2021; 22:e13303. [PMID: 34268868 DOI: 10.1111/obr.13303] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 01/19/2023]
Abstract
Previous reviews and clinical guidelines have identified 10-20 genetic syndromes associated with diabetes, but no systematic review has been conducted to date. We provide the first comprehensive catalog for syndromes with diabetes mellitus. We conducted a systematic review of MEDLINE, Embase, CENTRAL, PubMed, OMIM, and Orphanet databases for case reports, case series, and observational studies published between 1946 and January 15, 2020, that described diabetes mellitus in adults and children with monogenic or chromosomal syndromes. Our literature search identified 7,122 studies, of which 160 fulfilled inclusion criteria. Our analysis of these studies found 69 distinct diabetes syndromes. Thirty (43.5%) syndromes included diabetes mellitus as a cardinal clinical feature, and 56 (81.2%) were fully genetically elucidated. Sixty-three syndromes (91.3%) were described more than once in independent case reports, of which 59 (93.7%) demonstrated clinical heterogeneity. Syndromes associated with diabetes mellitus are more numerous and diverse than previously anticipated. While knowledge of the syndromes is limited by their low prevalence, future reviews will be needed as more cases are identified. The genetic etiologies of these syndromes are well elucidated and provide potential avenues for future gene identification efforts, aid in diagnosis and management, gene therapy research, and developing personalized medicine treatments.
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Affiliation(s)
- Daniel Shi
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Mehras Motamed
- Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Aurora Mejía-Benítez
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Leon Li
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Ethan Lin
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dalton Budhram
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Yuvreet Kaur
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, Nancy, France.,Faculty of Medicine of Nancy INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, France
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Zhang X, Robles H, Magee L K, Lorenz R M, Wang Z, Harris A C, Craft S C, Scheller L E. A bone-specific adipogenesis pathway in fat-free mice defines key origins and adaptations of bone marrow adipocytes with age and disease. eLife 2021; 10:66275. [PMID: 34378533 PMCID: PMC8412938 DOI: 10.7554/elife.66275] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 08/02/2021] [Indexed: 02/07/2023] Open
Abstract
Bone marrow adipocytes accumulate with age and in diverse disease states. However, their origins and adaptations in these conditions remain unclear, impairing our understanding of their context-specific endocrine functions and relationship with surrounding tissues. In this study, by analyzing bone and adipose tissues in the lipodystrophic ‘fat-free’ mouse, we define a novel, secondary adipogenesis pathway that relies on the recruitment of adiponectin-negative stromal progenitors. This pathway is unique to the bone marrow and is activated with age and in states of metabolic stress in the fat-free mouse model, resulting in the expansion of bone marrow adipocytes specialized for lipid storage with compromised lipid mobilization and cytokine expression within regions traditionally devoted to hematopoiesis. This finding further distinguishes bone marrow from peripheral adipocytes and contributes to our understanding of bone marrow adipocyte origins, adaptations, and relationships with surrounding tissues with age and disease.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, Saint Louis, United States.,Department of Biomedical Engineering, Washington University, Saint Louis, United States
| | - Hero Robles
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, Saint Louis, United States
| | - Kristann Magee L
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, Saint Louis, United States
| | - Madelyn Lorenz R
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, Saint Louis, United States
| | - Zhaohua Wang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, Saint Louis, United States.,Department of Orthopaedic Surgery, Washington University, Saint Louis, United States
| | - Charles Harris A
- Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine, Washington University, Saint Louis, United States
| | - Clarissa Craft S
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, Saint Louis, United States
| | - Erica Scheller L
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, Saint Louis, United States.,Department of Biomedical Engineering, Washington University, Saint Louis, United States
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Abaj F, Saeedy SAG, Mirzaei K. Are caveolin-1 minor alleles more likely to be risk alleles in insulin resistance mechanisms in metabolic diseases? BMC Res Notes 2021; 14:185. [PMID: 34001235 PMCID: PMC8130340 DOI: 10.1186/s13104-021-05597-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 05/05/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Obesity and insulin resistance (IR) are interrelated in a range of ways. The IR-obesity relationship is not a cause-and-effect association. Molecular biology research has made tremendous strides in discovering contributors to find this association. Genes that control adipocyte function such as caveolin-1 (CAV1); probably interact in the pathogenesis of human IR in this context. The involvement of CAV1 in glucose/lipid homeostasis is revealed and could modify the signaling of the insulin receptor. We examined the association between CAV1 and insulin signaling in modifying dyslipidemia and fat composition in overweight and obese women with a prevalent variant in the CAV1 gene. RESULTS Minor allele carriers were slightly older and had higher BMI (p = 0.02), FMI (p = 0.006), and VLF (p = 0.01) values; and tended to have lower total cholesterol TC (p = 0.04), low-density lipoprotein cholesterol (LDL-C) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p = 0.003). HOMA-IR levels predicted fat mass index (FMI) 0.47 (0.08, 0.87), visceral fat level (VFL) 0.65 (0.23, 1.07), TC 6.82 (1.76, 11.88) and HDL-C - 1.663 (- 3.11, - 0.214) only between minor allele carriers in adjusted models. (β, CI). Our results cast a new light on the IR mechanism and future studies will elucidate the clinical relevance of CAV1-IR in patients with dyslipidemia and high fat composition.
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Affiliation(s)
- Faezeh Abaj
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), No. 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, P.O. Box, 14155-6117, Tehran, Iran
| | | | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), No. 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, P.O. Box, 14155-6117, Tehran, Iran.
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González-Hódar L, McDonald JG, Vale G, Thompson BM, Figueroa AM, Tapia PJ, Robledo F, Agarwal AK, Garg A, Horton JD, Cortés V. Decreased caveolae in AGPAT2 lacking adipocytes is independent of changes in cholesterol or sphingolipid levels: A whole cell and plasma membrane lipidomic analysis of adipogenesis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166167. [PMID: 33989739 DOI: 10.1016/j.bbadis.2021.166167] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/19/2021] [Accepted: 05/04/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Adipocytes from lipodystrophic Agpat2-/- mice have impaired adipogenesis and fewer caveolae. Herein, we examined whether these defects are associated with changes in lipid composition or abnormal levels of caveolae-associated proteins. Lipidome changes were quantified in differentiated Agpat2-/- adipocytes to identify lipids with potential adipogenic roles. METHODS Agpat2-/- and wild type brown preadipocytes were differentiated in vitro. Plasma membrane was purified by ultracentrifugation. Number of caveolae and caveolae-associated proteins, as well as sterol, sphingolipid, and phospholipid lipidome were determined across differentiation. RESULTS Differentiated Agpat2-/- adipocytes had decreased caveolae number but conserved insulin signaling. Caveolin-1 and cavin-1 levels were equivalent between Agpat2-/- and wild type adipocytes. No differences in PM cholesterol and sphingolipids abundance were detected between genotypes. Levels of phosphatidylserine at day 10 of differentiation were increased in Agpat2-/- adipocytes. Wild type adipocytes had increased whole cell triglyceride, diacylglycerol, phosphatidylglycerol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine, and trihexosyl ceramide, and decreased 24,25-dihydrolanosterol and sitosterol, as a result of adipogenic differentiation. By contrast, adipogenesis did not modify whole cell neutral lipids but increased lysophosphatidylcholine, sphingomyelin, and trihexosyl ceramide levels in Agpat2-/- adipocytes. Unexpectedly, adipogenesis decreased PM levels of main phospholipids in both genotypes. CONCLUSION In Agpat2-/- adipocytes, decreased caveolae is not associated with changes in PM cholesterol nor sphingolipid levels; however, increased PM phosphatidylserine content may be implicated. Abnormal lipid composition is associated with the adipogenic abnormalities of Agpat2 -/- adipocytes but does not prevent insulin signaling.
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Affiliation(s)
- Lila González-Hódar
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, 8331150, Chile
| | - Jeffrey G McDonald
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, United States
| | - Goncalo Vale
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
| | - Bonne M Thompson
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
| | - Ana-María Figueroa
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, 8331150, Chile
| | - Pablo J Tapia
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, 8331150, Chile
| | - Fermín Robledo
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, 8331150, Chile
| | - Anil K Agarwal
- Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, TX 75390, United States
| | - Abhimanyu Garg
- Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, TX 75390, United States
| | - Jay D Horton
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, United States; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, United States.
| | - Víctor Cortés
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, 8331150, Chile.
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Hughes AE, Hattersley AT, Flanagan SE, Freathy RM. Two decades since the fetal insulin hypothesis: what have we learned from genetics? Diabetologia 2021; 64:717-726. [PMID: 33569631 PMCID: PMC7940336 DOI: 10.1007/s00125-021-05386-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/25/2020] [Indexed: 12/16/2022]
Abstract
In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.
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Affiliation(s)
- Alice E Hughes
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Andrew T Hattersley
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Sarah E Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Rachel M Freathy
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
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Araújo de Melo Campos JT, Dantas de Medeiros JL, Cardoso de Melo ME, Alvares da Silva M, Oliveira de Sena M, Sales Craveiro Sarmento A, Fassarella Agnez Lima L, de Freitas Fregonezi GA, Gomes Lima J. Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166120. [PMID: 33713793 DOI: 10.1016/j.bbadis.2021.166120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 01/17/2023]
Abstract
Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.
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Affiliation(s)
- Julliane Tamara Araújo de Melo Campos
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
| | - Jorge Luiz Dantas de Medeiros
- PneumoCardioVascular Lab/HUOL, Hospital Universitário Onofre Lopes, Empresa Brasileira de Serviços Hospitalares and Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
| | - Maria Eduarda Cardoso de Melo
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Monique Alvares da Silva
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Matheus Oliveira de Sena
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Aquiles Sales Craveiro Sarmento
- Unidade de Laboratório de Análises Clínicas e Anatomia Patológica, Hospital Universitário de Lagarto (HUL)/UFS, Lagarto, SE, Brazil
| | - Lucymara Fassarella Agnez Lima
- Laboratório de Biologia Molecular e Genômica, Departamento de Biologia Celular e Genética, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Guilherme Augusto de Freitas Fregonezi
- PneumoCardioVascular Lab/HUOL, Hospital Universitário Onofre Lopes, Empresa Brasileira de Serviços Hospitalares and Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil; Laboratório de Inovação Tecnológica em Reabilitação, Departamento de Fisioterapia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
| | - Josivan Gomes Lima
- Departamento de Medicina Clínica, Hospital Universitário Onofre Lopes (HUOL)/UFRN, Natal, RN, Brazil
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Xin J, Yan S, Hong X, Zhang H, Zha J. Environmentally relevant concentrations of carbamazepine induced lipid metabolism disorder of Chinese rare minnow (Gobiocypris rarus) in a gender-specific pattern. CHEMOSPHERE 2021; 265:129080. [PMID: 33261836 DOI: 10.1016/j.chemosphere.2020.129080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 11/01/2020] [Accepted: 11/19/2020] [Indexed: 06/12/2023]
Abstract
Carbamazepine (CBZ), an anticonvulsant and mood stabilizer, is ubiquitous distributed in aquatic environment. Though the toxicity and endocrine disrupting effect of CBZ on non-target organisms have been studied, its lipotoxity are scarcely known. To assess the lipotoxicity of CBZ, 2-month-old Chinese rare minnow were exposed to 0, 1, 10, and 100 μg/L CBZ for 90 d. Obvious dyslipidemia was observed after 30 d and 90 d exposure, whereas overt hyperlipidemia was observed in males at 100 μg/L treatments. Severe lipid droplet accumulation in livers was observed at 10 and 100 μg/L treatments for 30 d and in females, whereas those was observed at all treatments in males. In addition, serious mitochondria damage was observed in males at 100 μg/L treatments. After 90 d exposure, the enzyme activities of FAS and ACCα were significantly increased at 10 and 100 μg/L treatments, whereas HMGCR were markedly increased at 100 μg/L treatments (p < 0.05). However, ACCβ were markedly decreased in females at 10 and 100 μg/L treatments and in males at all treatments (p < 0.05). The transcription levels of fasn, accα, hmgcrα, fdft1, idi1, plin1, plin2, caveolin1, and caveolin2 were significantly increased at 100 μg/L treatments (p < 0.05). Moreover, the body weight was obviously increased at 10 and 100 μg/L treatments in males (p < 0.05). Our results confirmed that environmental relevant concentrations CBZ induced lipid metabolism disorder and mitochondria damage of Chinese rare minnow in a gender-specific pattern, which provided a new insight into the lipotoxicity mechanism of CBZ.
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Affiliation(s)
- Jiajing Xin
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Beijing Key Laboratory of Industrial Wastewater Treatment and Reuse, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100085, China
| | - Saihong Yan
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Beijing Key Laboratory of Industrial Wastewater Treatment and Reuse, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100085, China
| | - Xiangsheng Hong
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Beijing Key Laboratory of Industrial Wastewater Treatment and Reuse, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100085, China
| | - Huan Zhang
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agriculture University, Wuhan, 430070, China
| | - Jinmiao Zha
- Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Beijing Key Laboratory of Industrial Wastewater Treatment and Reuse, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100085, China.
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Abstract
Caveolae are specialised and dynamic plasma membrane subdomains, involved in many cellular functions including endocytosis, signal transduction, mechanosensing and lipid storage, trafficking, and metabolism. Two protein families are indispensable for caveola formation and function, namely caveolins and cavins. Mutations of genes encoding these caveolar proteins cause serious pathological conditions such as cardiomyopathies, skeletal muscle diseases, and lipodystrophies. Deregulation of caveola-forming protein expression is associated with many types of cancers including prostate cancer. The distinct function of secretion of the prostatic fluid, and the unique metabolic phenotype of prostate cells relying on lipid metabolism as a main bioenergetic pathway further suggest a significant role of caveolae and caveolar proteins in prostate malignancy. Accumulating in vitro, in vivo, and clinical evidence showed the association of caveolin-1 with prostate cancer grade, stage, metastasis, and drug resistance. In contrast, cavin-1 was found to exhibit tumour suppressive roles. Studies on prostate cancer were the first to show the distinct function of the caveolar proteins depending on their localisation within the caveolar compartment or as cytoplasmic or secreted proteins. In this review, we summarise the roles of caveola-forming proteins in prostate cancer and the potential of exploiting them as therapeutic targets or biological markers.
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Matthaeus C, Taraska JW. Energy and Dynamics of Caveolae Trafficking. Front Cell Dev Biol 2021; 8:614472. [PMID: 33692993 PMCID: PMC7939723 DOI: 10.3389/fcell.2020.614472] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 12/21/2020] [Indexed: 12/19/2022] Open
Abstract
Caveolae are 70–100 nm diameter plasma membrane invaginations found in abundance in adipocytes, endothelial cells, myocytes, and fibroblasts. Their bulb-shaped membrane domain is characterized and formed by specific lipid binding proteins including Caveolins, Cavins, Pacsin2, and EHD2. Likewise, an enrichment of cholesterol and other lipids makes caveolae a distinct membrane environment that supports proteins involved in cell-type specific signaling pathways. Their ability to detach from the plasma membrane and move through the cytosol has been shown to be important for lipid trafficking and metabolism. Here, we review recent concepts in caveolae trafficking and dynamics. Second, we discuss how ATP and GTP-regulated proteins including dynamin and EHD2 control caveolae behavior. Throughout, we summarize the potential physiological and cell biological roles of caveolae internalization and trafficking and highlight open questions in the field and future directions for study.
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Affiliation(s)
- Claudia Matthaeus
- Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Justin W Taraska
- Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
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50
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McGrath C, Little-Letsinger SE, Sankaran JS, Sen B, Xie Z, Styner MA, Zong X, Chen W, Rubin J, Klett EL, Coleman RA, Styner M. Exercise Increases Bone in SEIPIN Deficient Lipodystrophy, Despite Low Marrow Adiposity. Front Endocrinol (Lausanne) 2021; 12:782194. [PMID: 35145475 PMCID: PMC8822583 DOI: 10.3389/fendo.2021.782194] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/20/2021] [Indexed: 01/12/2023] Open
Abstract
Exercise, typically beneficial for skeletal health, has not yet been studied in lipodystrophy, a condition characterized by paucity of white adipose tissue, with eventual diabetes, and steatosis. We applied a mouse model of global deficiency of Bscl2 (SEIPIN), required for lipid droplet formation. Male twelve-week-old B6 knockouts (KO) and wild type (WT) littermates were assigned six-weeks of voluntary, running exercise (E) versus non-exercise (N=5-8). KO weighed 14% less than WT (p=0.01) and exhibited an absence of epididymal adipose tissue; KO liver Plin1 via qPCR was 9-fold that of WT (p=0.04), consistent with steatosis. Bone marrow adipose tissue (BMAT), unlike white adipose, was measurable, although 40.5% lower in KO vs WT (p=0.0003) via 9.4T MRI/advanced image analysis. SEIPIN ablation's most notable effect marrow adiposity was in the proximal femoral diaphysis (-56% KO vs WT, p=0.005), with relative preservation in KO-distal-femur. Bone via μCT was preserved in SEIPIN KO, though some quality parameters were attenuated. Running distance, speed, and time were comparable in KO and WT. Exercise reduced weight (-24% WT-E vs WT p<0.001) but not in KO. Notably, exercise increased trabecular BV/TV in both (+31%, KO-E vs KO, p=0.004; +14%, WT-E vs WT, p=0.006). The presence and distribution of BMAT in SEIPIN KO, though lower than WT, is unexpected and points to a uniqueness of this depot. That trabecular bone increases were achievable in both KO and WT, despite a difference in BMAT quantity/distribution, points to potential metabolic flexibility during exercise-induced skeletal anabolism.
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Affiliation(s)
- Cody McGrath
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Sarah E. Little-Letsinger
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jeyantt Srinivas Sankaran
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Buer Sen
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Zhihui Xie
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Martin A. Styner
- Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Xiaopeng Zong
- Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Weiqin Chen
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Janet Rubin
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- North Carolina Diabetes Research Center (NCDRC), Chapel Hill, NC, United States
| | - Eric L. Klett
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- North Carolina Diabetes Research Center (NCDRC), Chapel Hill, NC, United States
- Department of Nutrition, Gillings School of Global Public Health, UNC, Chapel Hill, NC, United States
| | - Rosalind A. Coleman
- Department of Nutrition, Gillings School of Global Public Health, UNC, Chapel Hill, NC, United States
| | - Maya Styner
- Department of Medicine, Division of Endocrinology & Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- North Carolina Diabetes Research Center (NCDRC), Chapel Hill, NC, United States
- *Correspondence: Maya Styner,
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