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Cheng JY, Cheng HY, Hung JT, Restrepo GM, Chiou SP, Shih LY, Yu AL, Kao HK, Yu J, Wei FC. Enhancing retention and quality of tissue stromal vascular fraction graft with globo H ceramide. Stem Cell Res Ther 2025; 16:317. [PMID: 40551154 PMCID: PMC12186370 DOI: 10.1186/s13287-025-04395-2] [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: 06/17/2024] [Accepted: 05/14/2025] [Indexed: 06/28/2025] Open
Abstract
BACKGROUND Fat grafting has been extensively used in plastic surgery practice, yet unstable retention in the recipient site remains a significant clinical challenge. The limited tolerance of injected adipose tissue to ischemia has prompted strategies aiming at timely enhancing the vascularity of the grafted fat. Various modified fat graft preparations have been used, and the mechanically processed tissue stromal vascular fraction (tSVF) derived from fat tissue has garnered considerable interest for enhancing rate of fat graft retention. Further enhancement of the graft retention and quality through supplements to tSVF is worthy of investigation. METHODS The arteriovenous (AV) shunt in rats has been used to evaluate tSVF in vivo. We employed this animal model to investigate the regenerative potential of glycolipid Globo H Ceramide (GHCer) added to tSVF isolated from male Lewis rats. Sixty-two rats divided into four groups were studied. Study parameters included gene expression of vascular endothelial growth factor A (VEGFA) and fatty acid binding protein 4 (FABP4), percentages of the CD45-CD31+ endothelial cell, fat tissue retention and fibrotic changes. In vitro studies on adipose-derived mesenchymal stromal cells (AD-MSCs) included angiogenesis by tube formation assay and adipogenesis. RESULTS The addition of GHCer resulted in superior retention of the tSVF grafts at one-, two-, and eight-week post-grafting (p < 0.05). Elevated expression VEGFA was observed from one week (p < 0.05), followed by FABP4 at two weeks post-grafting in the tSVF + GHCer grafts (p < 0.01). After eight weeks, the numbers of CD45-CD31+ endothelial cells and adipocytes were significantly increased in the tSVF + GHCer grafts (p < 0.01), while collagen deposition was reduced (p < 0.05). Given that GHCer potentially exerted its effects on tSVF through AD-MSCs within, we performed in vitro studies and demonstrated that GHCer promoted AD-MSC differentiation into neovessels (p < 0.05) and adipocytes (p < 0.001). CONCLUSIONS Supplementing GHCer to tSVF effectively reduced fat reabsorption and fibrotic changes of the grafts, while enhancing angiogenesis and adipogenesis, potentially through facilitating AD-MSC differentiation within tSVF. These findings support the potential clinical application of GHCer to enhance the stability and long-term outcomes of fat grafting procedures. TRIAL REGISTRATION Not applicable. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Jing-Yan Cheng
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Hui-Yun Cheng
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Gonzalo Mallarino Restrepo
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Shih-Pin Chiou
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Ling-Yi Shih
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
| | - Alice L Yu
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
- Medical College, Chang Gung University, Taoyuan, 333, Taiwan
- Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA
- Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan
| | - Huang-Kai Kao
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan
- Medical College, Chang Gung University, Taoyuan, 333, Taiwan
| | - John Yu
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.
- Medical College, Chang Gung University, Taoyuan, 333, Taiwan.
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, 115, Taiwan.
| | - Fu-Chan Wei
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.
- Medical College, Chang Gung University, Taoyuan, 333, Taiwan.
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Sun Y, Shan X, Li M, Niu Y, Sun Z, Ma X, Wang T, Zhang J, Niu D. Autoimmune mechanisms and inflammation in obesity-associated type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease. Funct Integr Genomics 2025; 25:84. [PMID: 40205260 DOI: 10.1007/s10142-025-01587-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/11/2025]
Abstract
Obesity, characterized by the excessive accumulation of white adipose tissue, is a significant global health burden and a major risk factor for a range of diseases, including malignancies and metabolic disorders. Individuals with high visceral fat content are particularly susceptible to severe complications such as type 2 diabetes, cardiovascular diseases, and liver disorders. However, the pathogenesis of obesity-related metabolic diseases extends beyond simple adiposity. Chronic obesity triggers a prolonged inflammatory response, which leads to tissue fibrosis and sustained organ damage, contributing to multi-organ dysfunction. This review explores the autoimmune mechanisms and inflammatory pathways underlying obesity-induced type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease, with an emphasis on their interrelated pathophysiology and the potential for therapeutic interventions.
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Grants
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- 2021C02068-4 Zhejiang Science and Technology Major Program on Agricultural New Variety Breeding
- 2021C02068-4 Zhejiang Science and Technology Major Program on Agricultural New Variety Breeding
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Affiliation(s)
- Yuanyuan Sun
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Xueting Shan
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Mingyang Li
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Yifan Niu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Zhongxin Sun
- Department of Plastic, Reconstructive & Hand Microsurgery, Ningbo NO.6 Hospital, Ningbo, 315000, Zhejiang, China
| | - Xiang Ma
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Tao Wang
- Nanjing Kgene Genetic Engineering Co., Ltd, Nanjing, 211300, Jiangsu, China.
| | - Jufang Zhang
- Department of Plastic and Aesthetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, China.
| | - Dong Niu
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China.
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Zaccaron RP, Mendes C, da Costa C, Silveira PCL, Rezin GT. Skin metabolism in obesity: A narrative review. Wound Repair Regen 2024; 32:1022-1027. [PMID: 39318160 DOI: 10.1111/wrr.13223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 08/20/2024] [Accepted: 09/09/2024] [Indexed: 09/26/2024]
Abstract
Obesity is a complex multifactorial disease in which excess body fat triggers negative health effects. Systemically, obesity causes several changes, such as inflammation, oxidative stress, mitochondrial dysfunction and apoptosis; factors linked to the slow and incomplete epithelial regenerative process. Specifically, in the integumentary system, obesity causes an expansion of the skin's surface area and changes in collagen deposition. Molecular underpinnings of why obesity delays wound healing are still poorly understood. In addition to the primary role of dermal adipocytes in lipid storage and heat insulation, they also promote skin immunity, wound healing and hair follicle cycling. As a consequence of the cellular and dysfunctional adaptations of adipocytes, inflammatory immune alterations, alteration in the expression of proteins genes associated with the blood supply, altered collagen formation through fibroblast senescence and excessive degradation of extracellular matrix proteins are metabolic characteristics of the system in obesity that contribute to sustained inflammation and decreased mechanical resistance of the skin.
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Affiliation(s)
- Rubya Pereira Zaccaron
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Tubarão, Santa Catarina, Brazil
| | - Carolini Mendes
- Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Santa Catarina, Brazil
| | - Camila da Costa
- Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Santa Catarina, Brazil
| | - Paulo Cesar Lock Silveira
- Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Santa Catarina, Brazil
| | - Gislaine Tezza Rezin
- Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Tubarão, Santa Catarina, Brazil
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Wang R, Gomez Salazar M, Pruñonosa Cervera I, Coutts A, French K, Pinto MM, Gohlke S, García-Martín R, Blüher M, Schofield CJ, Kourtzelis I, Stimson RH, Bénézech C, Christian M, Schulz TJ, Gudmundsson EF, Jennings LL, Gudnason VG, Chavakis T, Morton NM, Emilsson V, Michailidou Z. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality. Nat Commun 2024; 15:7483. [PMID: 39209825 PMCID: PMC11362468 DOI: 10.1038/s41467-024-51718-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.
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Affiliation(s)
- Rongling Wang
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Mario Gomez Salazar
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Iris Pruñonosa Cervera
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Amanda Coutts
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK
| | - Karen French
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Marlene Magalhaes Pinto
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Sabrina Gohlke
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany
| | - Ruben García-Martín
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC (CNB-CSIC), Campus-UAM, Madrid, Spain
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Christopher J Schofield
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford, Oxford, UK
| | - Ioannis Kourtzelis
- Hull York Medical School, York Biomedical Research Institute, University of York, York, UK
| | - Roland H Stimson
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Cécile Bénézech
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Mark Christian
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK
| | - Tim J Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | | | - Lori L Jennings
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Vilmundur G Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Triantafyllos Chavakis
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, Helmholtz Zentrum München, University Hospital and Faculty of Medicine Technische Universität Dresden, Dresden, Germany
| | - Nicholas M Morton
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK
| | - Valur Emilsson
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Zoi Michailidou
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK.
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5
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Vali A, Beaupère C, Loubaresse A, Dalle H, Fève B, Grosfeld A, Moldes M. Effects of glucocorticoids on adipose tissue plasticity. ANNALES D'ENDOCRINOLOGIE 2024; 85:259-262. [PMID: 38871499 DOI: 10.1016/j.ando.2024.05.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Glucocorticoids (GCs) play an important role in metabolic adaptation, regulating carbohydrate-lipid homeostasis and the immune system. Because they also have anti-inflammatory and immunosuppressive properties, synthetic analogues of GCs have been developed and are widely used in the treatment of chronic inflammatory conditions and in organ transplantation. GCs are among the most commonly prescribed drugs in the world. However, long term and high GC doses can cause side effects such as GC-induced diabetes and lipodystrophy. In recent years, a large number of independent studies have reported the effects of constitutive and adipocyte-specific deletion of the GC receptor (GR) in mice under different diets and treatments, resulting in contrasting phenotypes. To avoid potential compensatory mechanisms associated with the constitutive adipocyte GR silencing during adipose tissue development, our team has generated an inducible mouse model of GR deletion specifically in the adipocyte (AdipoGR-KO). Using this mouse model, we were able to demonstrate the critical role of the adipocyte GR in GC-induced metabolic changes. Indeed, under conditions of hypercorticism, AdipoGR-KO mice showed an improvement in glucose tolerance and insulin sensitivity, as well as in lipid profile, despite a massive increase in adiposity. This result is explained by a densification of adipose tissue vascularization, highlighting the repressive role of adipocyte GR in the healthy expansion of this tissue. Our work has largely contributed to the demonstration of the important role of the adipocyte GR in the physiology and pathophysiology of the adipose tissue and its impact on energy homeostasis.
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Affiliation(s)
- Anna Vali
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne université, Inserm, 75013 Paris, France
| | - Carine Beaupère
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne université, Inserm, 75013 Paris, France
| | - Alya Loubaresse
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne université, Inserm, 75013 Paris, France
| | - Héloïse Dalle
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne université, Inserm, 75013 Paris, France
| | - Bruno Fève
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne université, Inserm, 75013 Paris, France; Service endocrinologie, CRMR PRISIS, centre de recherche Saint-Antoine (CRSA), hôpital Saint-Antoine, AP-HP, Sorbonne université, Inserm, 75012 Paris, France
| | - Alexandra Grosfeld
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne université, Inserm, 75013 Paris, France
| | - Marthe Moldes
- Centre de recherche Saint-Antoine (CRSA), Sorbonne université, Inserm, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne université, Inserm, 75013 Paris, France.
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Vali A, Dalle H, Loubaresse A, Gilleron J, Havis E, Garcia M, Beaupère C, Denis C, Roblot N, Poussin K, Ledent T, Bouillet B, Cormont M, Tanti JF, Capeau J, Vatier C, Fève B, Grosfeld A, Moldes M. Adipocyte Glucocorticoid Receptor Activation With High Glucocorticoid Doses Impairs Healthy Adipose Tissue Expansion by Repressing Angiogenesis. Diabetes 2024; 73:211-224. [PMID: 37963392 DOI: 10.2337/db23-0165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 10/31/2023] [Indexed: 11/16/2023]
Abstract
In humans, glucocorticoids (GCs) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GCs often lead to side effects, including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)-deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion associated with a paradoxical improvement of metabolic health compared with control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of hypoxia-inducible factor 1α (HIF-1α) and proangiogenic vascular endothelial growth factor A (VEGFA) expression in GR-deficient adipocytes of AdipoGR-KO mice compared with control mice, together with an increased adipose vascular network, as assessed by three-dimensional imaging. GR activation reduced HIF-1α recruitment to the Vegfa promoter resulting from Hif-1α downregulation at the transcriptional and posttranslational levels. Importantly, in CORT-treated AdipoGR-KO mice, the blockade of VEGFA by a soluble decoy receptor prevented AT expansion and the healthy metabolic phenotype. Finally, in subcutaneous AT from patients with Cushing syndrome, higher VEGFA expression was associated with a better metabolic profile. Collectively, these results highlight that adipocyte GR negatively controls AT expansion and metabolic health through the downregulation of the major angiogenic effector VEGFA and inhibition of vascular network development. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Anna Vali
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Héloïse Dalle
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Alya Loubaresse
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Jérôme Gilleron
- Université Côte d'Azur, INSERM, C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Emmanuelle Havis
- Sorbonne Université, CNRS, INSERM, Laboratoire de Biologie du Développement, Institut Biologie Paris Seine, Paris, France
| | - Marie Garcia
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Carine Beaupère
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Clémentine Denis
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Natacha Roblot
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Karine Poussin
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Tatiana Ledent
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
| | - Benjamin Bouillet
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Mireille Cormont
- Université Côte d'Azur, INSERM, C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Jean-François Tanti
- Université Côte d'Azur, INSERM, C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Jacqueline Capeau
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Camille Vatier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Service Endocrinologie, CRMR PRISIS, Paris, France
| | - Bruno Fève
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Service Endocrinologie, CRMR PRISIS, Paris, France
| | - Alexandra Grosfeld
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
| | - Marthe Moldes
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France
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Gliniak CM, Pedersen L, Scherer PE. Adipose tissue fibrosis: the unwanted houseguest invited by obesity. J Endocrinol 2023; 259:e230180. [PMID: 37855264 PMCID: PMC11648981 DOI: 10.1530/joe-23-0180] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 09/27/2023] [Indexed: 09/28/2023]
Abstract
The prevalence of obesity is increasing exponentially across the globe. The lack of effective treatment options for long-term weight loss has magnified the enormity of this problem. Studies continue to demonstrate that adipose tissue holds a biological memory, one of the most important determinant of long-term weight maintenance. This phenomenon is consistent with the metabolically dynamic role of adipose tissue: it adapts and expands to store for excess energy and serves as an endocrine organ capable of synthesizing a number of biologically active molecules that regulate metabolic homeostasis. An important component of the plasticity of adipose tissue is the extracellular matrix, essential for structural support, mechanical stability, cell signaling and function. Chronic obesity upends a delicate balance of extracellular matrix synthesis and degradation, and the ECM accumulates in such a way that prevents the plasticity and function of the diverse cell types in adipose tissue. A series of maladaptive responses among the cells in adipose tissue leads to inflammation and fibrosis, major mechanisms that explain the link between obesity and insulin resistance, risk of type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Adipose tissue fibrosis persists after weight loss and further enhances adipose tissue dysfunction if weight is regained. Here, we highlight the current knowledge of the cellular events governing adipose tissue ECM remodeling during the development of obesity. Our goal is to delineate the relationship more clearly between adipose tissue ECM and metabolic disease, an important step toward better defining the pathophysiology of dysfunctional adipose tissue.
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Affiliation(s)
- Christy M Gliniak
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
| | - Line Pedersen
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
| | - Philipp E Scherer
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
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8
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Rana HS, Clabeaux CE, Patadia AH, Allen RC. The Overweight and Obese Patient in Oculofacial Plastic Surgery: A Narrative Review. Ophthalmic Plast Reconstr Surg 2023; 39:525-532. [PMID: 37010053 DOI: 10.1097/iop.0000000000002389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
PURPOSE The oculofacial plastic surgeon will more frequently encounter challenges related to overweight and obese patients as the incidence rises. There is a paucity of data in the oculofacial plastic surgical literature regarding this topic. The goal of this review is to detail the role obesity plays in the perioperative course and the considerations for a surgeon treating this patient population. METHODS The authors conducted a computerized search using PubMed, Embase, and Google Scholar. The search terms used were "(obesity OR overweight) AND surgery," "(obesity OR overweight) AND oculoplastic," "(obesity OR overweight) AND oculofacial," "(obesity OR overweight) AND 'facial plastic surgery', " "(obesity OR overweight) AND 'bariatric surgery', " "(obesity OR overweight) AND (pre-operative OR post-operative OR intraoperative," " (obesity OR overweight) AND complications," "(obesity OR overweight) AND (facial plastic surgery) AND complications)," "(obesity OR overweight) AND eyelid," "(obesity OR overweight) AND (nasolacrimal OR 'nasolacrimal duct')," "(obesity OR overweight) AND IIH," "(obesity OR overweight) AND exophthalmos." RESULTS A total of 127 articles, published from 1952 to 2022 in the English language or with English translations were included. Articles published earlier than 2000 were cited for foundational knowledge. References cited in the identified articles were also used to gather further data for the review. CONCLUSIONS Overweight and obese patients pose specific challenges that the oculofacial plastic surgeon should be aware of to better optimize patient outcomes. Multiple comorbidities, poor wound healing, and nutritional deficits all contribute to the complications experienced in this patient population. Further investigation on overweight and obese patients is needed.
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Affiliation(s)
- Harkaran S Rana
- Trauma and Emergency Subspecialty Surgeons, Denver, Colorado, U.S.A
| | - Carson E Clabeaux
- Department of Ophthalmology, Madigan Army Medical Center, Tacoma, Washington, U.S.A
| | - Amol H Patadia
- Trauma and Emergency Subspecialty Surgeons, Denver, Colorado, U.S.A
- Dr. Kiran C. Patel College of Allopathic Medicine, Davie, Florida, U.S.A
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Gong S, Li C, Leng Q, Liu C, Zhu Y, Zhang H, Li X. Inhibition of the mTORC1 pathway alleviates adipose tissue fibrosis. Heliyon 2023; 9:e21526. [PMID: 38034664 PMCID: PMC10681937 DOI: 10.1016/j.heliyon.2023.e21526] [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: 07/25/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 12/02/2023] Open
Abstract
Background Adipose fibrosis is a major factor of adipose dysfunction, which causes metabolic dysfunction during obesity, but its molecular mechanisms are poorly understood. This study investigated the role and potential mechanisms of mTORC1 in obesity-induced adipose fibrosis. Methods ob/ob mice were injected with rapamycin or the same volume of normal saline. The level of fibrosis in epididymal adipose tissue (EAT) was detected by observing aberrant deposition of extracellular matrix. Expression of fibrotic related genes was analysed using RNA-seq. 3T3-L1 preadipocytes were treated with cobalt chloride (CoCl2) and TGF-β1 to induce preadipocyte fibrosis. The fibrosis-related gene expression and protein levels were determined by RT-PCR, WB, and immunofluorescence in two types of fibrotic preadipocytes with or without rapamycin. Results Compared with vehicle treatment, EAT fibrosis-related aberrant deposition of extracellular matrix proteins and fibrotic gene expression were reduced in ob/ob mice treated with rapamycin. Both CoCl2-induced hypoxia and TGF-β1 successfully promoted adipocyte fibrosis, and the upregulated fibrosis-related genes expression was inhibited after the mTORC1 pathway was inhibited by rapamycin. Conclusion Inhibition of the mTORC1 pathway ameliorates adipose fibrosis by suppressing fibrosis-related genes in hypoxia- and TGF-β-induced fibrotic preadipocytes.
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Affiliation(s)
- Sa Gong
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
- Shanghai Songjiang District Fangta Hospital of Traditional Chinese Medicine, Shanghai, 201600, China
| | - Chang Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Qingyang Leng
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Chongxiao Liu
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Yi Zhu
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Hongli Zhang
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Xiaohua Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
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Abstract
The understanding of the mechanisms of liver fibrosis has been dominated by models in which chronic hepatocellular injury is the initiating step as is seen with viral infections. The increased prevalence of the metabolic syndrome, and the increases in liver fibrosis due to metabolic syndrome driven non-alcoholic steatohepatitis (NASH), has made it a priority to understand how this type of liver fibrosis is similar to, and different from, pure hepatocellular injury driven liver fibrosis. Both types of liver fibrosis have the transformation of the hepatic stellate cell (HSC) into a myofibroblast as a key step. In metabolic syndrome, there is little evidence that metabolite changes such as high levels of glucose and free fatty acids are directly inducing HSC transdifferentiation, however, metabolite changes may lead to reductions in immunomodulatory and hepatoprotective molecules such as lipoxins, resolvins and Interleukin (IL)-22. Cells of the innate immune system are known to be important intermediaries between hepatocellular damage and HSC transdifferentiation, primarily by producing cytokines such as transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF). Resident and infiltrating macrophages are the dominant innate immune cells, but others (dendritic cells, neutrophils, natural killer T cells and mucosal-associated invariant T cells) also have important roles in inducing and resolving liver fibrosis. CD8+ and CD4+ T cells of the adaptive immune system have been identified to have greater profibrotic roles than previously realised by inducing hepatocyte death (auto-aggressive CD8+T) cells and cytokines producing (TH17 producing CD4+T) cells. Finally, the cellular networks present in NASH fibrosis are being identified and suggest that once fibrosis has developed cell-to-cell communication is dominated by myofibroblasts autocrine signalling followed by communication with cholangiocytes and endothelial cells, with myofibroblast-hepatocyte, and myofibroblast-macrophage signalling having minor roles. Such information is essential to the development of antifibrotic strategies for different stages of fibrosis.
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Affiliation(s)
- Wajahat Mehal
- Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
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Davidson CT, Miller E, Muir M, Dawson JC, Lee M, Aitken S, Serrels A, Webster SP, Homer NZM, Andrew R, Brunton VG, Hadoke PWF, Walker BR. 11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis. PLoS One 2023; 18:e0255709. [PMID: 36940215 PMCID: PMC10027213 DOI: 10.1371/journal.pone.0255709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/05/2022] [Indexed: 03/21/2023] Open
Abstract
Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11β-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11β-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11β-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.
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Affiliation(s)
- Callam T. Davidson
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Eileen Miller
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Morwenna Muir
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - John C. Dawson
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Martin Lee
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Stuart Aitken
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Alan Serrels
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Scott P. Webster
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Natalie Z. M. Homer
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Edinburgh Mass Spectrometry Core, Clinical Research Facility, University of Edinburgh, Edinburgh, United Kingdom
| | - Ruth Andrew
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Valerie G. Brunton
- Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Patrick W. F. Hadoke
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Brian R. Walker
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Institute of Genetic Medicine, Newcastle University, Newcastle University, Newcastle upon Tyne, United Kingdom
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Yang L, Gilbertsen A, Xia H, Benyumov A, Smith K, Herrera J, Racila E, Bitterman PB, Henke CA. Hypoxia enhances IPF mesenchymal progenitor cell fibrogenicity via the lactate/GPR81/HIF1α pathway. JCI Insight 2023; 8:e163820. [PMID: 36656644 PMCID: PMC9977506 DOI: 10.1172/jci.insight.163820] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 01/11/2023] [Indexed: 01/20/2023] Open
Abstract
Hypoxia is a sentinel feature of idiopathic pulmonary fibrosis (IPF). The IPF microenvironment contains high lactate levels, and hypoxia enhances cellular lactate production. Lactate, acting through the GPR81 lactate receptor, serves as a signal molecule regulating cellular processes. We previously identified intrinsically fibrogenic mesenchymal progenitor cells (MPCs) that drive fibrosis in the lungs of patients with IPF. However, whether hypoxia enhances IPF MPC fibrogenicity is unclear. We hypothesized that hypoxia increases IPF MPC fibrogenicity via lactate and its cognate receptor GPR81. Here we show that hypoxia promotes IPF MPC self-renewal. The mechanism involves hypoxia-mediated enhancement of LDHA function and lactate production and release. Hypoxia also increases HIF1α levels, and this increase in turn augments the expression of GPR81. Exogenous lactate operating through GPR81 promotes IPF MPC self-renewal. IHC analysis of IPF lung tissue demonstrates IPF MPCs expressing GPR81 and hypoxic markers on the periphery of the fibroblastic focus. We show that hypoxia enhances IPF MPC fibrogenicity in vivo. We demonstrate that knockdown of GPR81 inhibits hypoxia-induced IPF MPC self-renewal in vitro and attenuates hypoxia-induced IPF MPC fibrogenicity in vivo. Our data demonstrate that hypoxia creates a feed-forward loop that augments IPF MPC fibrogenicity via the lactate/GPR81/HIF1α pathway.
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Affiliation(s)
| | | | | | | | - Karen Smith
- CSENG Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Emil Racila
- Department of Laboratory Medicine and Pathology, Minneapolis, Minnesota, USA
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13
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Na S, Mazzaferro N, Xia W, Greenberg P, Beckerman W. Risk Factors for Surgical Site Infections After Lower Extremity Open Revascularization. Ann Vasc Surg 2023; 89:251-260. [PMID: 36404450 DOI: 10.1016/j.avsg.2022.09.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/01/2022] [Accepted: 09/19/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Surgical site infection (SSI) is a serious complication of lower extremity open revascularization and is associated with increased morbidity, increased healthcare costs, and decreased postoperative quality of life. The objective of this study was to determine factors associated with an increased risk of developing postoperative SSI in patients undergoing lower extremity revascularization. Associations between SSI and postoperative complications were also identified. METHODS Patients who underwent lower extremity open revascularization from 2014-2017 were identified using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). A multivariate logistic regression analysis was used to determine risk factors associated with SSIs within 30 days of the operation and postoperative complications. Odds ratios (ORs) were adjusted for demographics, preoperative comorbidities, procedure type, and intraoperative variables. RESULTS Ten thousand nine hundred ten patients who underwent lower extremity open revascularization were identified, with a mean age of 67.24 years and of whom 7,318 (67%) were male. Of the 10,910 patients, 922 (8.45%) had an SSI within 30 days of the operation. Risk factors associated with developing SSI included body mass index 25-29.9 (OR, 1.34; 95% confidence interval [CI], 1.08-1.67), body mass index ≥ 30 (OR, 2.12; 95% CI, 1.71-2.62), history of severe chronic obstructive pulmonary disease (OR, 1.47; 95% CI, 1.18-1.84), preprocedural beta-blocker use (OR, 1.25; CI 95%, 1.05-1.49), procedure time > 214 minutes (OR, 1.44; 95% CI, 1.22-1.70), and creatinine > 1.2 (OR 1.03; 95% CI, 0.87-1.21). One factor associated with a decreased risk of developing SSI was male gender (OR, 0.71; 95% CI, 0.60-0.84). Patients who developed an SSI were more likely to have adverse outcomes such as myocardial infarction/stroke, major amputation, bleeding requiring transfusion or secondary procedure, or require a reintervention in the treated segment. CONCLUSIONS There are various patient-related and operative factors that increase the likelihood of developing an SSI after lower extremity open revascularization. These findings indicate that addressing modifiable perioperative SSI risk factors may be beneficial in decreasing rates of SSI and improving postoperative outcomes.
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Affiliation(s)
- Sungshin Na
- Division of Vascular Surgery and Endovascular Therapy, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ.
| | - Natale Mazzaferro
- Biostatistics and Epidemiology Services Center, Rutgers School of Public Health, Rutgers University, Piscataway, NJ; Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Rutgers University, Piscataway, NJ
| | - Weiyi Xia
- Biostatistics and Epidemiology Services Center, Rutgers School of Public Health, Rutgers University, Piscataway, NJ; Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Rutgers University, Piscataway, NJ
| | - Patricia Greenberg
- Biostatistics and Epidemiology Services Center, Rutgers School of Public Health, Rutgers University, Piscataway, NJ; Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Rutgers University, Piscataway, NJ
| | - William Beckerman
- Division of Vascular Surgery and Endovascular Therapy, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
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Inhibition of 11β-hydroxysteroid dehydrogenase 1 relieves fibrosis through depolarizing of hepatic stellate cell in NASH. Cell Death Dis 2022; 13:1011. [PMID: 36446766 PMCID: PMC9709168 DOI: 10.1038/s41419-022-05452-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/10/2022] [Accepted: 11/17/2022] [Indexed: 12/02/2022]
Abstract
11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. Although 11βHSD1 has been implicated in numerous metabolic syndromes, such as obesity and diabetes, the functional roles of 11βHSD1 during progression of nonalcoholic steatohepatitis (NASH) and consequent fibrosis have not been fully elucidated. We found that pharmacological and genetic inhibition of 11βHSD1 resulted in reprogramming of hepatic stellate cell (HSC) activation via inhibition of p-SMAD3, α-SMA, Snail, and Col1A1 in a fibrotic environment and in multicellular hepatic spheroids (MCHSs). We also determined that 11βHSD1 contributes to the maintenance of NF-κB signaling through modulation of TNF, TLR7, ITGB3, and TWIST, as well as regulating PPARα signaling and extracellular matrix accumulation in activated HSCs during advanced fibrogenesis in MCHSs. Of great interest, the 11βHSD1 inhibitor J2H-1702 significantly attenuated hepatic lipid accumulation and ameliorated liver fibrosis in diet- and toxicity-induced NASH mouse models. Together, our data indicate that J2H-1702 is a promising new clinical candidate for the treatment of NASH.
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15
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Aird R, Wills J, Roby KF, Bénézech C, Stimson RH, Wabitsch M, Pollard JW, Finch A, Michailidou Z. Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation. Front Endocrinol (Lausanne) 2022; 13:989523. [PMID: 36329893 PMCID: PMC9623062 DOI: 10.3389/fendo.2022.989523] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/15/2022] [Indexed: 12/05/2022] Open
Abstract
Objective Obesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (breast and ovarian metastasis in the omentum). The obesogenic and tumour micro-environment share a common pathogenic feature, oxygen deprivation (hypoxia). Here we test how hypoxia changes the metabolome of adipocytes to assist cancer cell growth. Methods Human and mouse breast and ovarian cancer cell lines were co-cultured with human and mouse adipocytes respectively under normoxia or hypoxia. Proliferation and lipid uptake in cancer cells were measured by commercial assays. Metabolite changes under normoxia or hypoxia were measured in the media of human adipocytes by targeted LC/MS. Results Hypoxic cancer-conditioned media increased lipolysis in both human and mouse adipocytes. This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on HIF1α expression in adipocytes, as mouse adipocytes lacking HIF1α showed blunted responses under hypoxic conditions. Targeted metabolomics of the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes media revealed that culture with hypoxic-conditioned media from non-malignant mammary epithelial cells (MCF10A) can alter the adipocyte metabolome and drive proliferation of the non-malignant cells. Conclusion Here, we show that hypoxia in the adipose-tumour microenvironment is the driving force of the lipid uptake in both mammary and ovarian cancer cells. Hypoxia can modify the adipocyte metabolome towards accelerated lipolysis, glucose deprivation and reduced ketosis. These metabolic shifts in adipocytes could assist both mammary epithelial and cancer cells to bypass the inhibitory effects of hypoxia on proliferation and thrive.
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Affiliation(s)
- R. Aird
- University/British Heart Foundation (BHF) Centre for Cardiovascular Science, Edinburgh University, Edinburgh, United Kingdom
| | - J. Wills
- MRC Institute of Genetics and Molecular Medicine, Edinburgh University, Edinburgh, United Kingdom
| | - K. F. Roby
- University of Kansas Medical Center, Kansas City, Kansas, KS, United States
| | - C. Bénézech
- University/British Heart Foundation (BHF) Centre for Cardiovascular Science, Edinburgh University, Edinburgh, United Kingdom
| | - R. H. Stimson
- University/British Heart Foundation (BHF) Centre for Cardiovascular Science, Edinburgh University, Edinburgh, United Kingdom
| | - M. Wabitsch
- University Medical Center Department of Pediatrics and Adolescent Medicine, Ulm, Germany
| | - J. W. Pollard
- Medical Research Council (MRC) Centre for Reproductive Health, Edinburgh University, Edinburgh, United Kingdom
| | - A. Finch
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Z. Michailidou
- University/British Heart Foundation (BHF) Centre for Cardiovascular Science, Edinburgh University, Edinburgh, United Kingdom
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16
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Wu J, Miller E, Davidson C, Walker BR, Hadoke PWF. Enhanced Angiogenesis by 11βHSD1 Blockage Is Insufficient to Improve Reperfusion Following Hindlimb Ischaemia. Front Cardiovasc Med 2022; 8:795823. [PMID: 35097015 PMCID: PMC8790072 DOI: 10.3389/fcvm.2021.795823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Critical limb ischaemia (CLI), which is estimated to affect 2 million people in the United States, reduces quality of life, is associated with high morbidity and mortality, and has limited treatment options. Direct stimulation of angiogenesis using proangiogenic growth factors has been investigated as a therapeutic strategy to improve reperfusion in the ischaemic leg. Despite positive outcomes in animal studies, there has been little success in clinical translation. This investigation addressed the hypothesis that angiogenesis could be stimulated indirectly in the ischaemic hindlimb by blocking 11β-hydroxysteroid dehydrogenase 1 (11βHSD1)-mediated reactivation of anti-angiogenic glucocorticoids. Method and Results: Corticosterone suppressed ex vivo angiogenesis in the mouse aortic ring assay. 11βHSD1 deletion (Hsd11b1Del1/Del1) or pharmacological inhibition (with 300 nM UE2316) which block the reactivation of glucocorticoid (i.e., the conversion of 11-dehydrocorticosterone (11DHC) to bioactive corticosterone) significantly reduced 11DHC-induced suppression of angiogenesis. In a sponge implantation model, 11βHSD1 deletion, but not pharmacological inhibition, enhanced inflammation-induced angiogenesis. By contrast, in the mouse hindlimb ischaemia model, post-ischaemic reperfusion and vascular density were not affected by either deletion or pharmacological inhibition of 11βHSD1 in young or aged mice. 3D vascular imaging suggested that hind limb reperfusion in the 1st week following induction of ischaemia may be driven by the rapid expansion of collateral arteries rather than by angiogenesis. Conclusion: 11βHSD1-mediated glucocorticoid reactivation suppressed angiogenesis ex vivo and in vivo. However, regulation of angiogenesis alone was insufficient to promote reperfusion in hindlimb ischaemia. Future investigation of post-ischaemic reperfusion should include other aspects of systemic vascular remodeling including arteriogenesis and collateral formation.
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Affiliation(s)
- Junxi Wu
- The Queen's Medical Research Institute, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom,Department of Biomedical Engineering, University of Strathclyde, Glasgow, United Kingdom
| | - Eileen Miller
- The Queen's Medical Research Institute, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Callam Davidson
- The Queen's Medical Research Institute, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Brian R. Walker
- The Queen's Medical Research Institute, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Patrick W. F. Hadoke
- The Queen's Medical Research Institute, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom,*Correspondence: Patrick W. F. Hadoke
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Marcelin G, Clément K. The multifaceted progenitor fates in healthy or unhealthy adipose tissue during obesity. Rev Endocr Metab Disord 2021; 22:1111-1119. [PMID: 34105090 DOI: 10.1007/s11154-021-09662-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/01/2021] [Indexed: 10/21/2022]
Abstract
While obesity is defined as an excessive fat accumulation conferring a risk to metabolic health, increased adipose mass by itself does not fully explain obesity's propensity to promote metabolic alterations. Adipose tissue regulates multiple processes critical for energy homeostasis and its dysfunction favors the development and perpetuation of metabolic diseases. Obesity drives inflammatory leucocyte infiltration in adipose tissue and fibrotic transformation of the fat depots. Both features associate with metabolic alterations such as impaired glucose control and resistance to fat mass loss. In this context, adipose progenitors, an heterogenous resident population of mesenchymal stromal cells, display functions important to shape healthy or unhealthy adipose tissue expansion. We, here, outline the current understanding of adipose progenitor biology in the context of obesity-induced adipose tissue remodeling.
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Affiliation(s)
- Geneviève Marcelin
- Nutrition and Obesities : Systemic Approaches (NutriOmics, UMRS U1269), Sorbonne Universités, INSERM, Paris, France
| | - Karine Clément
- Nutrition and Obesities : Systemic Approaches (NutriOmics, UMRS U1269), Sorbonne Universités, INSERM, Paris, France.
- Nutrition Department, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, CRNH Ile de France, 75013, Paris, France.
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Todorčević M, Manuel AR, Austen L, Michailidou Z, Hazlehurst JM, Neville M, Stradling JR, Karpe F. Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese. Int J Obes (Lond) 2021; 45:1618-1622. [PMID: 33758342 PMCID: PMC8236405 DOI: 10.1038/s41366-021-00793-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 02/01/2021] [Accepted: 02/11/2021] [Indexed: 01/15/2023]
Abstract
It has been suggested that metabolic dysfunction in obesity is at least in part driven by adipose tissue (AT) hypoxia. However, studies on AT hypoxia in humans have shown conflicting data. Therefore we aimed to investigate if markers of AT hypoxia were present in the subcutaneous AT of severly obese individuals (class III obesity) with and without hypoventilation syndrome (OHS) in comparison to moderately obese (class I obesity) and lean controls. To provide a proof-of-concept study, we quantified AT hypoxia by hypoxia inducible factor 1 A (HIF1A) protein abundance in human participants ranging from lean to severly obese (class III obesity). On top of that nightly arterial O2 saturation in individuals with obesity OHS was assessed. Subjects with class III obesity (BMI > 40 kg/m2) and OHS exhibited significantly higher adipose HIF1A protein levels versus those with class I obesity (BMI 30-34.9 kg/m2) and lean controls whereas those with class III obesity without OHS showed an intermediate response. HIF1A gene expression was not well correlated with protein abundance. Although these data demonstrate genuine AT hypoxia in the expected pathophysiological context of OHS, we did not observe a hypoxia signal in lesser degrees of obesity suggesting that adipose dysfunction may not be driven by hypoxia in moderate obesity.
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Affiliation(s)
- Marijana Todorčević
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Ari R Manuel
- Oxford Respiratory Trials Unit, Churchill Hospital, University of Oxford, Oxford, UK
- Liverpool Centre for Respiratory Science, University of Liverpool, Liverpool, UK
| | - Luke Austen
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Zoi Michailidou
- Queen's Medical Research, Institute Centre for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
| | - Jonathan M Hazlehurst
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Matt Neville
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - John R Stradling
- Oxford Respiratory Trials Unit, Churchill Hospital, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, OUH Trust, Churchill Hospital, Oxford, UK
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
- NIHR Oxford Biomedical Research Centre, OUH Trust, Churchill Hospital, Oxford, UK.
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19
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Lee SG, Kim JS, Kim HJ, Schlaepfer DD, Kim IS, Nam JO. Endothelial angiogenic activity and adipose angiogenesis is controlled by extracellular matrix protein TGFBI. Sci Rep 2021; 11:9644. [PMID: 33958649 PMCID: PMC8102489 DOI: 10.1038/s41598-021-88959-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 04/05/2021] [Indexed: 12/14/2022] Open
Abstract
Several studies have suggested that extracellular matrix (ECM) remodeling and the microenvironment are tightly associated with adipogenesis and adipose angiogenesis. In the present study, we demonstrated that transforming growth factor-beta induced (TGFBI) suppresses angiogenesis stimulated by adipocyte-conditioned medium (Ad-CM), both in vitro and in vivo. TGFBI knockout (KO) mice exhibited increased numbers of blood vessels in adipose tissue, and blood vessels from these mice showed enhanced infiltration into Matrigel containing Ad-CM. The treatment of Ad-CM-stimulated SVEC-10 endothelial cells with TGFBI protein reduced migration and tube-forming activity. TGFBI protein suppressed the activation of the Src and extracellular signaling-related kinase signaling pathways of these SVEC-10 endothelial cells. Our findings indicated that TGFBI inhibited adipose angiogenesis by suppressing the activation of Src and ERK signaling pathways, possibly because of the stimulation of the angiogenic activity of endothelial cells.
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Affiliation(s)
- Seul Gi Lee
- Department of Food Science and Biotechnology, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Jin Soo Kim
- National Institute for Korean Medicine Development, Kyeongsan, 38540, Republic of Korea
| | - Ha-Jeong Kim
- Department of Physiology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea
| | - David D Schlaepfer
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA
| | - In-San Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea.,Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Ju-Ock Nam
- Department of Food Science and Biotechnology, Kyungpook National University, Daegu, 41566, Republic of Korea.
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20
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Li L, Wei Y, Fang C, Liu S, Zhou F, Zhao G, Li Y, Luo Y, Guo Z, Lin W, Yang W. Exercise retards ongoing adipose tissue fibrosis in diet-induced obese mice. Endocr Connect 2021; 10:325-335. [PMID: 33617465 PMCID: PMC8052575 DOI: 10.1530/ec-20-0643] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/17/2021] [Indexed: 02/06/2023]
Abstract
Exercise has been recommended as an important strategy to improve glucose metabolism in obesity. Adipose tissue fibrosis is associated with inflammation and is implicated in glucose metabolism disturbance and insulin resistance in obesity. However, the effect of exercise on the progression of adipose tissue fibrosis is still unknown. The aim of the present study was to investigate whether exercise retarded the progression of adipose tissue fibrosis and ameliorated glucose homeostasis in diet-induced obese mice. To do so, obesity and adipose tissue fibrosis in mice were induced by high-fat diet feeding for 12 weeks and the mice subsequently received high-fat diet and exercise intervention for another 12 weeks. Exercise alleviated high-fat diet-induced glucose intolerance and insulin resistance. Continued high-fat diet feeding exacerbated collagen deposition and further increased fibrosis-related gene expression in adipose tissue. Exercise attenuated or reversed these changes. Additionally, PPARγ, which has been shown to inhibit adipose tissue fibrosis, was observed to be increased following exercise. Moreover, exercise decreased the expression of HIF-1α in adipose fibrosis, and adipose tissue inflammation was inhibited. In conclusion, our data indicate that exercise attenuates and even reverses the progression of adipose tissue fibrosis, providing a plausible mechanism for its beneficial effects on glucose metabolism in obesity.
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Affiliation(s)
- Liangming Li
- Center for Scientific Research and Institute of Exercise and Health, Guangzhou Sport University, Guangzhou, China
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Yuan Wei
- Center for Scientific Research and Institute of Exercise and Health, Guangzhou Sport University, Guangzhou, China
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Chunlu Fang
- Center for Scientific Research and Institute of Exercise and Health, Guangzhou Sport University, Guangzhou, China
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Shujing Liu
- Center for Scientific Research and Institute of Exercise and Health, Guangzhou Sport University, Guangzhou, China
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Fu Zhou
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Ge Zhao
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Yaping Li
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Yuan Luo
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Ziyi Guo
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
| | - Weiqun Lin
- Department of Clinical Nutrition, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wenqi Yang
- Center for Scientific Research and Institute of Exercise and Health, Guangzhou Sport University, Guangzhou, China
- Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, China
- Correspondence should be addressed to W Yang:
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21
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Wang R, Zhou W, Zhu X, Zhou N, Yang F, Sun B, Li X. Differences in Neuregulin 4 Expression in Children: Effects of Fat Depots and Obese Status. Endocr Res 2020; 45:190-201. [PMID: 31986906 DOI: 10.1080/07435800.2020.1721528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE To observe the expression of Nrg4, uncoupling protein-1 (UCP1), tumor necrosis factor α (TNFα), CD31, VE-cadherin/CDH5 and vascular endothelial growth factor A (VEGF-A) mRNA in abdominal subcutaneous (SC), omental (OM) adipose tissue in children with relation to anthropometric parameters. Further to verify the effect of inflammatory mediators on Nrg4 and UCP1 mRNA expression in adipocytes. METHODS Paired SC and OM adipose tissues were obtained from 58 children. In vitro, the adipocytes isolated from primary inguinal adipose tissue of mice were treated with TNFα (50 ng/ml) for 12-48 h. mRNA levels of Nrg4, UCP1 and TNFα were determined by real-time PCR. RESULTS Nrg4, UCP1, VEGF-A and CDH5 mRNA levels in SC were significantly higher than those in OM adipose tissue and the mRNA level of TNFα showed the opposite result. Moreover, Nrg4 and UCP1 mRNA in SC were significantly lower in overweight children compared to normal weight children. Nrg4 in SC and OM was negatively associated with BMISDS, WHtR. CDH55 mRNA in OM was negatively associated with WHR. VEGF-A was positively correlated with Nrg4 in SC. In vitro, Nrg4 and UCP1 mRNA levels in adipocytes were dose- and time-dependently decreased under TNFα treatment. CONCLUSIONS Nrg4, UCP1, VEGF-A and CDH5 mRNA expression in adipose tissues display a depot-specific pattern. Nrg4 mRNA levels in adipose tissue are decreased with obesity and associated with WAT browning and angiogenesis. TNFα may be involved in the regulation of Nrg4 level in adipose tissue, which may be one of the causes of the down-regulation of Nrg4 expression in obesity with chronic inflammatory response.
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Affiliation(s)
- Ran Wang
- Department of Children Health Care, Children's Hospital of Nanjing Medical University , Nanjing, China
| | - Wei Zhou
- Department of Children Health Care, Children's Hospital of Nanjing Medical University , Nanjing, China
| | - Xiaolei Zhu
- Department of Children Health Care, Children's Hospital of Nanjing Medical University , Nanjing, China
| | - Nan Zhou
- Department of Children Health Care, Children's Hospital of Nanjing Medical University , Nanjing, China
| | - Fan Yang
- Department of Children Health Care, Children's Hospital of Nanjing Medical University , Nanjing, China
| | - Bin Sun
- Department of General Surgery, Children's Hospital of Nanjing Medical University , Nanjing, China
| | - Xiaonan Li
- Department of Children Health Care, Children's Hospital of Nanjing Medical University , Nanjing, China
- Institute of Pediatric Research, Nanjing Medical University , Nanjing, China
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22
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Marcelin G, Silveira ALM, Martins LB, Ferreira AV, Clément K. Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis. J Clin Invest 2020; 129:4032-4040. [PMID: 31498150 DOI: 10.1172/jci129192] [Citation(s) in RCA: 182] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Obesity originates from an imbalance between caloric intake and energy expenditure that promotes adipose tissue expansion, which is necessary to buffer nutrient excess. Patients with higher visceral fat mass are at a higher risk of developing severe complications such as type 2 diabetes and cardiovascular and liver diseases. However, increased fat mass does not fully explain obesity's propensity to promote metabolic diseases. With chronic obesity, adipose tissue undergoes major remodeling, which can ultimately result in unresolved chronic inflammation leading to fibrosis accumulation. These features drive local tissue damage and initiate and/or maintain multiorgan dysfunction. Here, we review the current understanding of adipose tissue remodeling with a focus on obesity-induced adipose tissue fibrosis and its relevance to clinical manifestations.
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Affiliation(s)
- Geneviève Marcelin
- Nutrition and Obesities: Systemic Approaches (NutriOmics, UMRS U1269), INSERM, Sorbonne Université, Paris, France
| | - Ana Letícia M Silveira
- Nutrition and Obesities: Systemic Approaches (NutriOmics, UMRS U1269), INSERM, Sorbonne Université, Paris, France.,Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Laís Bhering Martins
- Nutrition and Obesities: Systemic Approaches (NutriOmics, UMRS U1269), INSERM, Sorbonne Université, Paris, France.,Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Adaliene Vm Ferreira
- Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Karine Clément
- Nutrition and Obesities: Systemic Approaches (NutriOmics, UMRS U1269), INSERM, Sorbonne Université, Paris, France.,Nutrition Department, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France
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23
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Tseilikman V, Dremencov E, Tseilikman O, Pavlovicova M, Lacinova L, Jezova D. Role of glucocorticoid- and monoamine-metabolizing enzymes in stress-related psychopathological processes. Stress 2020; 23:1-12. [PMID: 31322459 DOI: 10.1080/10253890.2019.1641080] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Glucocorticoid signaling is fundamental in healthy stress coping and in the pathophysiology of stress-related diseases, such as post-traumatic stress disorder (PTSD). Glucocorticoids are metabolized by cytochrome P450 (CYP) as well as 11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and 2 (11βHSD2). Acute stress-induced increase in glucocorticoid concentrations stimulates the expression of several CYP sub-types. CYP is primarily responsible for glucocorticoid metabolism and its increased activity can result in decreased circulating glucocorticoids in response to repeated stress stimuli. In addition, repeated stress-induced glucocorticoid release can promote 11βHSD1 activation and 11βHSD2 inhibition, and the 11βHSD2 suppression can lead to apparent mineralocorticoid excess. The activation of CYP and 11βHSD1 and the suppression of 11βHSD2 may at least partly contribute to development of the blunted glucocorticoid response to stressors characteristic in high trait anxiety, PTSD, and other stress-related disorders. Glucocorticoids and glucocorticoid-metabolizing enzymes interact closely with other biomolecules such as inflammatory cytokines, monoamines, and some monoamine-metabolizing enzymes, namely the monoamine oxidase type A (MAO-A) and B (MAO-B). Glucocorticoids boost MAO activity and this decreases monoamine levels and induces oxidative tissue damage which then activates inflammatory cytokines. The inflammatory cytokines suppress CYP expression and activity. This dynamic cross-talk between glucocorticoids, monoamines, and their metabolizing enzymes could be a critical factor in the pathophysiology of stress-related disorders.Lay summaryGlucocorticoids, which are produced and released under the control by brain regulatory centers, are fundamental in the stress response. This review emphasizes the importance of glucocorticoid metabolism and particularly the interaction between the brain and the liver as the major metabolic organ in the body. The activity of enzymes involved in glucocorticoid metabolism is proposed to play not only an important role in positive, healthy glucocorticoid effects, but also to contribute to the development and course of stress-related diseases.
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Affiliation(s)
- Vadim Tseilikman
- School of Medical Biology, South Ural State University, Chelyabinsk, Russia
| | - Eliyahu Dremencov
- School of Medical Biology, South Ural State University, Chelyabinsk, Russia
- Institute of Molecular Physiology and Genetics, Centre for Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Olga Tseilikman
- School of Medical Biology, South Ural State University, Chelyabinsk, Russia
| | - Michaela Pavlovicova
- Institute of Molecular Physiology and Genetics, Centre for Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lubica Lacinova
- Institute of Molecular Physiology and Genetics, Centre for Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
- Faculty of Natural Sciences, University of Saints Cyril and Methodius, Trnava, Slovakia
| | - Daniela Jezova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
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24
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Michailidou Z. Fundamental roles for hypoxia signalling in adipose tissue metabolism and inflammation in obesity. CURRENT OPINION IN PHYSIOLOGY 2019. [DOI: 10.1016/j.cophys.2019.09.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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25
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Phuong TTT, Walker AE, Henson GD, Machin DR, Li DY, Donato AJ, Lesniewski LA. Deletion of Robo4 prevents high-fat diet-induced adipose artery and systemic metabolic dysfunction. Microcirculation 2019; 26:e12540. [PMID: 30825241 DOI: 10.1111/micc.12540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/22/2019] [Accepted: 02/27/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Accumulating evidence suggests the vascular endothelium plays a fundamental role in the pathophysiology of obesity by regulating the functional status of white adipose and systemic metabolism. Robo4 is expressed specifically in endothelial cells and increases vascular stability and inhibits angiogenesis. We sought to determine the role of Robo4 in modulating cardiometabolic function in response to high-fat feeding. METHODS We examined exercise capacity, glucose tolerance, and white adipose tissue artery gene expression, endothelium-dependent dilation (EDD), and angiogenesis in wild type and Robo4 knockout (KO) mice fed normal chow (NC) or a high-fat diet (HFD). RESULTS We found Robo4 deletion enhances exercise capacity in NC-fed mice and HFD markedly increased the expression of the Robo4 ligand, Slit2, in white adipose tissue. Deletion of Robo4 increased angiogenesis in white adipose tissue and protected against HFD-induced impairments in white adipose artery vasodilation and glucose intolerance. CONCLUSIONS We demonstrate a novel functional role for Robo4 in endothelial cell function and metabolic homeostasis in white adipose tissue, with Robo4 deletion protecting against endothelial and metabolic dysfunction associated with a HFD. Our findings suggest that Robo4-dependent signaling pathways may be a novel target in anti-obesity therapy.
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Affiliation(s)
- Tam T T Phuong
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah
| | - Ashley E Walker
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah
| | - Grant D Henson
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah
| | - Daniel R Machin
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah
| | - Dean Y Li
- Department of Medicine, Program in Molecular Medicine, University of Utah, Salt Lake City, Utah.,Division of Cardiovascular Medicine Department of Medicine, University of Utah, Salt Lake City, Utah.,Department of Human Genetics, University of Utah, Salt Lake City, Utah
| | - Anthony J Donato
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah.,Salt Lake City Veteran's Affair Medical Center, Geriatrics Research Education and Clinic Center, Salt Lake City, Utah.,Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Lisa A Lesniewski
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah.,Salt Lake City Veteran's Affair Medical Center, Geriatrics Research Education and Clinic Center, Salt Lake City, Utah.,Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
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26
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Sudhakar M, Silambanan S, Prabhakaran AA, Ramakrishnan R. Angiogenic Potential, Circulating Angiogenic Factors and Insulin Resistance in Subjects with Obesity. Indian J Clin Biochem 2019; 36:43-50. [PMID: 33505126 DOI: 10.1007/s12291-019-0816-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 01/28/2019] [Indexed: 11/25/2022]
Abstract
Altered vascular function and pathological angiogenesis are important factors common to the development of obesity and obesity-associated diseases. Most human studies relating obesity and angiogenesis have compared levels of angiogenic factors in obesity without looking at the serum angiogenic capacity which reflects the balance between the effects of angiogenic and angiostatic factors. Therefore, in this cross-sectional study, the serum angiogenic potential and levels of angiogenic factors in serum of obese (BMI > 25 kg/m2) and lean subjects (BMI < 23 kg/m2), with no history of obesity associated co-morbidities, were assessed. Serum angiogenic potential was significantly higher (p < 0.0001) in both male (n = 67) and female (n = 35) obese subjects and showed a positive correlation (r = 0.4, p < 0.0001) with BMI. Serum levels of the angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin were significantly higher in obese subjects. Levels of angiostatic factors such as angiostatin, endostatin were not altered in obese male subjects but were elevated in female obese subjects. Angiogenic potential and levels of VEGF did not vary in obese subjects with high HOMA-IR compared to obese subjects with low HOMA-IR. These results suggest that the angiogenic potential of serum was elevated in obesity and that insulin resistance may not contribute to the increased angiogenic potential in obesity.
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Affiliation(s)
- Manu Sudhakar
- Department of Biochemistry, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu India
| | - Santhi Silambanan
- Department of Biochemistry, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu India
| | - Athira A Prabhakaran
- Inter University Centre for Genomics and Gene Technology, Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala India
| | - Ramya Ramakrishnan
- Department of Surgery, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu India
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27
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Medela AMB, Penton A, Bostrom KI, Saparov A, Jumabay M. Generation of Vascular Networks from Adipocytes In Vitro. INTERNATIONAL JOURNAL OF CELL SCIENCE & MOLECULAR BIOLOGY 2019; 6:555684. [PMID: 33954280 PMCID: PMC8095932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Multipotent cells derived from white mature adipocytes, referred to as dedifferentiated fat (DFAT) cells have the capacity differentiate into endothelial cells. The objective of this study was to modify the isolation method for DFAT cells in order to optimize the endothelial lineage potential. The adipocytes were preincubated for 24 hours, washed, and then incubated for 5 days to allow the generated DFAT cells to remain in proximity to the adipocytes while the cells aggregated into cell clusters. The DFAT cells rapidly differentiated into adipocytes after which endothelial-like cells (ECs) emerged and formed tube-like structure closely associated with the newly differentiated adipocytes. The lipid-filled cells then gradually disappeared whereas the network of tube structure expanded over the course of 3 weeks. ECs accounted for 35-45% of the cells derived from the DFAT cells, as assessed by qPCR, immunofluorescence and fluorescence-activated cell sorting. The DFAT cell-derived ECs could also be further enriched by magnetic sorting, thereby serving as a mouse cell line for further research.
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Affiliation(s)
| | - Ashley Penton
- Division of Cardiology, David Geffen School of Medicine at UCLA, USA
| | | | - Arman Saparov
- Department of Medicine, Nazarbayev University School of Medicine, Kazakhstan
| | - Medet Jumabay
- Division of Cardiology, David Geffen School of Medicine at UCLA, USA,Corresponding author: Medet Jumabay, Division of Cardiology, David Geffen School of Medicine at UCLA, Box 951679, Los Angeles, CA 90095-1679
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28
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Abstract
Obesity prevalence continues to rise worldwide, posing a substantial burden on people's health. However, up to 45% of obese individuals do not suffer from cardiometabolic complications, also called the metabolically healthy obese (MHO). Concurrently, up to 30% of normal-weight individuals demonstrate cardiometabolic risk factors that are generally observed in obese individuals, the metabolically obese normal weight (MONW). Besides lifestyle, environmental factors and demographic factors, innate biological mechanisms are known to contribute to the aetiology of the MHO and MONW phenotypes, as well. Experimental studies in animal models have shown that adipose tissue expandability, fat distribution, adipogenesis, adipose tissue vascularization, inflammation and fibrosis, and mitochondrial function are the main mechanisms that uncouple adiposity from its cardiometabolic comorbidities. We reviewed current genetic association studies to expand insights into the biology of MHO/MONW phenotypes. At least four genetic loci were identified through genome-wide association studies for body fat percentage (BF%) of which the BF%-increasing allele was associated with a protective effect on glycemic and lipid outcomes. For some, this association was mediated through favourable effects on body fat distribution. Other studies that characterized the genetic susceptibility of insulin resistance found that a higher susceptibility was associated with lower overall adiposity due to less fat accumulation at hips and legs, suggesting that an impaired capacity to store fat subcutaneously or a preferential storage in the intra-abdominal cavity may be metabolically harmful. Clearly, more work remains to be done in this field, first through gene discovery and subsequently through functional follow-up of identified genes.
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Affiliation(s)
- R J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Copenhagen, Denmark
| | - T O Kilpeläinen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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29
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Bousquenaud M, Fico F, Solinas G, Rüegg C, Santamaria-Martínez A. Obesity promotes the expansion of metastasis-initiating cells in breast cancer. Breast Cancer Res 2018; 20:104. [PMID: 30180888 PMCID: PMC6123990 DOI: 10.1186/s13058-018-1029-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 07/19/2018] [Indexed: 12/16/2022] Open
Abstract
Background Obesity is a strong predictor of poor prognosis in breast cancer, especially in postmenopausal women. In particular, tumors in obese patients tend to seed more distant metastases, although the biology behind this observation remains poorly understood. Methods To elucidate the effects of the obese microenvironment on metastatic spread, we ovariectomized C57BL/6 J female mice and fed them either a regular diet (RD) or a high-fat diet (HFD) to generate a postmenopausal diet-induced obesity model. We then studied tumor progression to metastasis of Py230 and EO771 grafts. We analyzed and phenotyped the RD and HFD tumors and the surrounding adipose tissue by flow cytometry, qPCR, immunohistochemistry (IHC) and western blot. The influence of the microenvironment on tumor cells was assessed by performing cross-transplantation of RD and HFD tumor cells into other RD and HFD mice. The results were analyzed using the unpaired Student t test when comparing two variables, otherwise we used one-way or two-way analysis of variance. The relationship between two variables was calculated using correlation coefficients. Results Our results show that tumors in obese mice grow faster, are also less vascularized, more hypoxic, of higher grade and enriched in CD11b+Ly6G+ neutrophils. Collectively, this favors induction of the epithelial-to-mesenchymal transition and progression to claudin-low breast cancer, a subtype of triple-negative breast cancer that is enriched in cancer stem cells. Interestingly, transplanting HFD-derived tumor cells in RD mice transfers enhanced tumor growth and lung metastasis formation. Conclusions These data indicate that a pro-metastatic effect of obesity is acquired by the tumor cells in the primary tumor independently of the microenvironment of the secondary site. Graphical abstract Effects of postmenopausal obesity on primary breast cancer tumoursᅟ![]() Electronic supplementary material The online version of this article (10.1186/s13058-018-1029-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mélanie Bousquenaud
- Experimental and Translational Oncology Laboratory, Division of Pathology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Flavia Fico
- Tumor Ecology Laboratory, Division of Pathology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700, Fribourg, Switzerland
| | - Giovanni Solinas
- Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Curzio Rüegg
- Experimental and Translational Oncology Laboratory, Division of Pathology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.,Swiss Integrative Center for Human Health, Fribourg, Switzerland
| | - Albert Santamaria-Martínez
- Tumor Ecology Laboratory, Division of Pathology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700, Fribourg, Switzerland.
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Zou X, Ramachandran P, Kendall TJ, Pellicoro A, Dora E, Aucott RL, Manwani K, Man TY, Chapman KE, Henderson NC, Forbes SJ, Webster SP, Iredale JP, Walker BR, Michailidou Z. 11Beta-hydroxysteroid dehydrogenase-1 deficiency or inhibition enhances hepatic myofibroblast activation in murine liver fibrosis. Hepatology 2018; 67:2167-2181. [PMID: 29251794 PMCID: PMC6001805 DOI: 10.1002/hep.29734] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 11/16/2017] [Accepted: 12/07/2017] [Indexed: 12/13/2022]
Abstract
A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11βHSD1). Although 11βHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11βHSD1 deficiency (global, Hsd11b1-/- , and hepatic myofibroblast-specific, Hsd11b1fl/fl /Pdgfrb-cre) 11βHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1fl/fl /albumin-cre mice did not differ from that of controls, ruling out 11βHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1α1, an effect attenuated by the 11βHSD1 inhibitor [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone. HSCs from Hsd11b1-/- and Hsd11b1fl/fl /Pdgfrb-cre mice expressed higher levels of Acta2 and Col1α1 and were correspondingly more potently activated. In vivo [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone administration prior to chemical injury recapitulated findings in Hsd11b1-/- mice, including greater fibrosis. CONCLUSION 11βHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11βHSD1 inhibitors on liver injury and repair are likely to be context-dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (Hepatology 2018;67:2167-2181).
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Affiliation(s)
- Xiantong Zou
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | | | - Timothy J. Kendall
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | | | - Elena Dora
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Rebecca L. Aucott
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Kajal Manwani
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Tak Yung Man
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Karen E. Chapman
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Neil C. Henderson
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Stuart J. Forbes
- MRC Centre for Regenerative MedicineQueen's Medical Research InstituteEdinburghUK
| | - Scott P. Webster
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - John P. Iredale
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
| | - Brian R. Walker
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
| | - Zoi Michailidou
- BHF Centre for Cardiovascular ScienceThe University of EdinburghEdinburghUK
- MRC Centre for Inflammation ResearchThe University of EdinburghEdinburghUK
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Varlamov O, Bishop CV, Handu M, Takahashi D, Srinivasan S, White A, Roberts CT. Combined androgen excess and Western-style diet accelerates adipose tissue dysfunction in young adult, female nonhuman primates. Hum Reprod 2018; 32:1892-1902. [PMID: 28854720 DOI: 10.1093/humrep/dex244] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 06/26/2017] [Indexed: 12/21/2022] Open
Abstract
STUDY QUESTION What are the separate and combined effects of mild hyperandrogenemia and consumption of a high-fat Western-style diet (WSD) on white adipose tissue (WAT) morphology and function in young adult female nonhuman primates? SUMMARY ANSWER Combined exposure to mild hyperandrogenemia and WSD induces visceral omental (OM-WAT) but not subcutaneous (SC-WAT) adipocyte hypertrophy that is associated with increased uptake and reduced mobilization of free fatty acids. WHAT IS KNOWN ALREADY Mild hyperandrogenemia in females, principally in the context of polycystic ovary syndrome, is often associated with adipocyte hypertrophy, but the mechanisms of associated WAT dysfunction and depot specificity remain poorly understood. STUDY DESIGN, SIZE AND DURATION Female rhesus macaques were randomly assigned at 2.5 years of age (near menarche) to receive either cholesterol (C; n = 20) or testosterone (T; n = 20)-containing silastic implants to elevate T levels 5-fold above baseline. Half of each of these groups was then fed either a low-fat monkey chow diet or WSD, resulting in four treatment groups (C, control diet; T alone; WSD alone; T + WSD; n = 10/group) that were maintained until the current analyses were performed at 5.5 years of age (3 years of treatment, young adults). PARTICIPANTS/MATERIALS, SETTING AND METHODS OM and SC-WAT biopsies were collected and analyzed longitudinally for in vivo changes in adipocyte area and blood vessel density, and ex vivo basal and insulin-stimulated fatty acid uptake and basal and isoproterenol-stimulated lipolysis. MAIN RESULTS AND THE ROLE OF CHANCE In years 2 and 3 of treatment, the T + WSD group exhibited a significantly greater increase in OM adipocyte size compared to all other groups (P < 0.05), while the size of SC adipocytes measured at the end of the study was not significantly different between groups. In year 3, both WAT depots from the WSD and T + WSD groups displayed a significant reduction in local capillary length and vessel junction density (P < 0.05). In year 3, insulin-stimulated fatty acid uptake in OM-WAT was increased in the T + WSD group compared to year 2 (P < 0.05). In year 3, basal lipolysis was blunted in the T and T + WSD groups in both WAT depots (P < 0.01), while isoproterenol-stimulated lipolysis was significantly blunted in the T and T + WSD groups only in SC-WAT (P < 0.01). LIMITATIONS, REASONS FOR CAUTION At this stage of the study, subjects were still relatively young adults, so that the effects of mild hyperandrogenemia and WSD may become more apparent with increasing age. WIDER IMPLICATIONS OF THE FINDINGS The combination of mild hyperandrogenemia and WSD accelerates the development of WAT dysfunction through T-specific (suppression of lipolytic response by T), WSD-dependent (reduced capillary density) and combined T + WSD (increased fatty acid uptake) mechanisms. These data support the idea that combined hyperandrogenemia and WSD increases the risk of developing obesity in females. STUDY FUNDING/COMPETING INTEREST(S) Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number P50 HD071836 to C.T.R. and award number OD 011092 from the Office of the Director, National Institutes of Health, for operation of the Oregon National Primate Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Affiliation(s)
- Oleg Varlamov
- Division of Cardiometabolic Health, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
| | - Cecily V Bishop
- Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
| | - Mithila Handu
- Division of Cardiometabolic Health, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
| | - Diana Takahashi
- Division of Cardiometabolic Health, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
| | - Sathya Srinivasan
- Division of Cardiometabolic Health, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
| | - Ashley White
- Division of Cardiometabolic Health, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA
| | - Charles T Roberts
- Division of Cardiometabolic Health, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA.,Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA.,Department of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
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Svendstrup M, Appel EVR, Sandholt CH, Ahluwalia TS, Ängquist LH, Thuesen BH, Jørgensen ME, Pedersen O, Grarup N, Hansen T, Sørensen TIA, Vestergaard H. Prospective Studies Exploring the Possible Impact of an ID3 Polymorphism on Changes in Obesity Measures. Obesity (Silver Spring) 2018; 26:747-754. [PMID: 29442437 DOI: 10.1002/oby.22109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 11/07/2017] [Accepted: 12/07/2017] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Changes in fat mass depend on adipogenesis and angiogenesis, mechanisms regulated by the inhibitor of differentiation-3 (ID3). Id3 knockout mice showed attenuated increases in BMI and visceral fat mass. We hypothesized that the ID3 missense variant (rs11574-A) would lead to an attenuated increase over time in fat mass, BMI, waist circumference (WC), and waist-hip ratio (WHR) in humans. METHODS The genotyped study populations included the Obesity Research Group - Genetics (ORGGEN) cohort, a cohort of men with obesity (N = 716) and of randomly selected men (N = 826) from the Danish draft register who were examined at mean ages of 20 and 46 years, and the Inter99 (N = 6,116) and Health2006 (N = 2,761) cohorts, two population-based samples of middle-aged people, followed up after 5 years. RESULTS In meta-analyses of all data, no association was found between rs11574-A and changes in BMI, WC, WHR, or fat mass. We found an association between rs11574-A and cross-sectional BMI (N = 10,359, β: -0.16 kg/m2 per allele, 95% CI: -0.30 to -0.01, P = 0.033) and fat mass (N = 4,188, β: -0.52 kg/m2 per allele, 95% CI: -1.03 to -0.01, P = 0.046). CONCLUSIONS No consistent impact of the genetic variant on changes in fat mass, BMI, or fat distribution was found in three Danish cohorts.
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Affiliation(s)
- Mathilde Svendstrup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
- Danish Diabetes Academy, Odense, Denmark
| | - Emil V R Appel
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
| | - Camilla H Sandholt
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
| | - Tarunveer S Ahluwalia
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Denmark
| | - Lars H Ängquist
- Department of Clinical Epidemiology, Bispebjerg and Frederiksberg Hospital, The Capital Region, Denmark
| | - Betina H Thuesen
- Research Center for Prevention and Health, Glostrup Hospital, Glostrup, Denmark
| | | | - Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
| | - Thorkild I A Sørensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
- Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Henrik Vestergaard
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Denmark
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Verma M, Kipari TMJ, Zhang Z, Man TY, Forster T, Homer NZM, Seckl JR, Holmes MC, Chapman KE. 11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation. Brain Behav Immun 2018; 69:223-234. [PMID: 29162555 PMCID: PMC5871395 DOI: 10.1016/j.bbi.2017.11.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 10/16/2017] [Accepted: 11/17/2017] [Indexed: 12/19/2022] Open
Abstract
Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.
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Affiliation(s)
- Manu Verma
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Tiina M J Kipari
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Zhenguang Zhang
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Tak Yung Man
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Thorsten Forster
- Division of Infection and Pathway Medicine, University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK
| | - Natalie Z M Homer
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Mass Spectrometry Core, Edinburgh Clinical Research Facility, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Jonathan R Seckl
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Megan C Holmes
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Karen E Chapman
- University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
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Zhang Z, Coutinho AE, Man TY, Kipari TMJ, Hadoke PWF, Salter DM, Seckl JR, Chapman KE. Macrophage 11β-HSD-1 deficiency promotes inflammatory angiogenesis. J Endocrinol 2017; 234:291-299. [PMID: 28676523 PMCID: PMC5574305 DOI: 10.1530/joe-17-0223] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 07/04/2017] [Indexed: 12/25/2022]
Abstract
11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11β-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11β-HSD1 deficiency or inhibition. However, 11β-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11β-HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM-Cre mediated deletion of Hsd11b1 to investigate whether 11β-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11β-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5 Thus, 11β-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11β-HSD1 in macrophages may be beneficial in tissue repair.
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Affiliation(s)
- Zhenguang Zhang
- University/BHF Centre for Cardiovascular ScienceThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Agnes E Coutinho
- University/BHF Centre for Cardiovascular ScienceThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Tak Yung Man
- University/BHF Centre for Cardiovascular ScienceThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Tiina M J Kipari
- Centre for Genomic and Experimental MedicineMRC Institute of Genetic and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Patrick W F Hadoke
- University/BHF Centre for Cardiovascular ScienceThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Donald M Salter
- Centre for Genomic and Experimental MedicineMRC Institute of Genetic and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Jonathan R Seckl
- University/BHF Centre for Cardiovascular ScienceThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Karen E Chapman
- University/BHF Centre for Cardiovascular ScienceThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
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Wang F, Han L, Qin RR, Zhang YY, Wang D, Wang ZH, Tang MX, Zhang Y, Zhong M, Zhang W. Overexpressing STAMP2 attenuates adipose tissue angiogenesis and insulin resistance in diabetic ApoE -/- /LDLR -/- mouse via a PPARγ/CD36 pathway. J Cell Mol Med 2017. [PMID: 28631352 PMCID: PMC5706521 DOI: 10.1111/jcmm.13233] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The aim of this study was to investigate whether overexpression of STAMP2 improves insulin resistance by regulating angiogenesis in adipose tissues. The characteristics of diabetic mice were measured by serial metabolite and pathology tests. Samples were obtained from epididymal, subcutaneous and brown adipose tissues. Histological and morphological analysis demonstrated that STAMP2 gene overexpression reduced adipocyte size, angiogenesis in epididymal and brown adipose tissues. On aortic ring assay, microvessels sprouting from aortas were significantly inhibited after STAMP2 gene overexpression. The cellular effect of STAMP2 on angiogenesis was explored in human umbilical vein endothelial cells (HUVECs) model. Correlation of STAMP2 and angiogenesis was validated by Ad‐STAMP2 transfection and STAMP2 siRNA inhibition. In vitro, overexpression of STAMP2 significantly inhibited endothelial cell migration, tube formation. The effects of Ad‐STAMP2 transfection on HUVECs were abolished by treatment with PPARγ antagonist GW9662 (2.5 μM), and the roles of STAMP2 siRNA on HUVECs were also reversed by treatment with PPARγ agonist rosiglitazone (RSG) (0.1 mM). RT‐PCR indicated that STAMP2 could regulate levels of adhesion molecules, vascular endothelial growth factor A and CD36. The expression of PPARγ and CD36 was decreased when STAMP2 was inhibited by siRNA, while PPARγ and CD36 were highly expressed after overexpression of STAMP2. Our results suggested that STAMP2 gene overexpression may improve insulin resistance via attenuating angiogenesis in epididymal and brown adipose tissues through the PPARγ/CD36 signalling pathway.
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Affiliation(s)
- Feng Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lu Han
- Department of General Practice, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ran-Ran Qin
- Department of Geriatric Medicines, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yao-Yuan Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Di Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Zhi-Hao Wang
- Department of Geriatric Medicines, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Meng-Xiong Tang
- Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ming Zhong
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Wei Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
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Breier G, Chavakis T, Hirsch E. Angiogenesis in metabolic-vascular disease. Thromb Haemost 2017; 117:1289-1295. [PMID: 28594427 DOI: 10.1160/th17-05-0325] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 05/29/2017] [Indexed: 12/15/2022]
Abstract
Angiogenesis, literally formation of new blood vessels, is the main process through which the vascular system expands during embryonic and postnatal development. Endothelial cells, which constitute the inner lining of all blood vessels, are typically in a quiescent state in the healthy adult organism. However, in vascular and metabolic diseases, the endothelium becomes unstable and dysfunctional. The resulting tissue hypoxia may thereby induce pathological angiogenesis, which is a hallmark of disease conditions like cancer or diabetic retinopathy. However, recent evidence suggests that angiogenesis is also a major player in the context of further metabolic diseases, especially in obesity. In particular, deregulated angiogenesis is linked with adipose tissue dysfunction and insulin resistance. On the other hand, signalling pathways, such as the PI3K pathway, may regulate metabolic activities in the endothelium. Endothelial cell metabolism emerges as an important regulator of angiogenesis. This review summarises the role of angiogenesis in metabolic-vascular disease, with specific focus on the role of angiogenesis in obesity-related metabolic dysfunction and on signaling pathways, especially PI3K, linking cell metabolism to endothelial function.
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Affiliation(s)
| | - Triantafyllos Chavakis
- Triantafyllos Chavakis, Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany, E-mail:
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An YA, Sun K, Joffin N, Zhang F, Deng Y, Donzé O, Kusminski CM, Scherer PE. Angiopoietin-2 in white adipose tissue improves metabolic homeostasis through enhanced angiogenesis. eLife 2017; 6. [PMID: 28355132 PMCID: PMC5391203 DOI: 10.7554/elife.24071] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/28/2017] [Indexed: 01/12/2023] Open
Abstract
Despite many angiogenic factors playing crucial roles in metabolic homeostasis, effects of angiopoietin-2 (ANG-2) in adipose tissue (AT) remain unclear. Utilizing a doxycycline-inducible AT-specific ANG-2 overexpression mouse model, we assessed the effects of ANG-2 in AT expansion upon a high-fat diet (HFD) challenge. ANG-2 is significantly induced, with subcutaneous white AT (sWAT) displaying the highest ANG-2 expression. ANG-2 overexpressing mice show increased sWAT vascularization and are resistant to HFD-induced obesity. In addition, improved glucose and lipid metabolism are observed. Mechanistically, the sWAT displays a healthier expansion pattern with increased anti-inflammatory macrophage infiltration. Conversely, ANG-2 neutralization in HFD-challenged wild-type mice shows reduced vascularization in sWAT, associated with impaired glucose tolerance and lipid clearance. Blocking ANG-2 causes significant pro-inflammatory and pro-fibrotic changes, hallmarks of an unhealthy AT expansion. In contrast to other pro-angiogenic factors, such as vascular endothelial growth factor-A (VEGF-A), this is achieved without any enhanced beiging of white AT. DOI:http://dx.doi.org/10.7554/eLife.24071.001
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Affiliation(s)
- Yu A An
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States
| | - Kai Sun
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States.,Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, United States
| | - Nolwenn Joffin
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States
| | - Fang Zhang
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States.,Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yingfeng Deng
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States
| | | | - Christine M Kusminski
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, United States.,Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, United States
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Shields KJ, Verdelis K, Passineau MJ, Faight EM, Zourelias L, Wu C, Chong R, Benza RL. Three-dimensional micro computed tomography analysis of the lung vasculature and differential adipose proteomics in the Sugen/hypoxia rat model of pulmonary arterial hypertension. Pulm Circ 2017; 6:586-596. [PMID: 28090302 DOI: 10.1086/688931] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling. The obesity epidemic has produced great interest in the relationship between small visceral adipose tissue depots producing localized inflammatory conditions, which may link metabolism, innate immunity, and vascular remodeling. This study used novel micro computed tomography (microCT) three-dimensional modeling to investigate the degree of remodeling of the lung vasculature and differential proteomics to determine small visceral adipose dysfunction in rats with severe PAH. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) with subsequent hypoxia exposure for 3 weeks (SU/hyp). At 12 weeks after hypoxia, microCT analysis showed a decrease in the ratio of vascular to total tissue volume within the SU/hyp group (mean ± standard deviation: 0.27 ± 0.066; P = 0.02) with increased vascular separation (0.37 ± 0.062 mm; P = 0.02) when compared with the control (0.34 ± 0.084 and 0.30 ± 0.072 mm). Differential proteomics detected an up-regulation of complement protein 3 (C3; SU/hyp∶control ratio = 2.86) and the adipose tissue-specific fatty acid binding protein-4 (FABP4, 2.66) in the heart adipose of the SU/hyp. Significant remodeling of the lung vasculature validates the efficacy of the SU/hyp rat for modeling human PAH. The upregulation of C3 and FABP4 within the heart adipose implicates small visceral adipose dysfunction. C3 has been associated with vascular stiffness, and FABP4 suppresses peroxisome proliferator-activated receptor, which is a major regulator of adipose function and known to be downregulated in PAH. These findings reveal that small visceral adipose tissue within the SU/hyp model provides mechanistic links for vascular remodeling and adipose dysfunction in the pathophysiology of PAH.
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Affiliation(s)
- Kelly J Shields
- Lupus Center of Excellence, Autoimmunity Institute, Department of Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Kostas Verdelis
- Craniofacial Regeneration Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Michael J Passineau
- Cardiovascular Institute, Department of Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Erin M Faight
- Lupus Center of Excellence, Autoimmunity Institute, Department of Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Lee Zourelias
- Cardiovascular Institute, Department of Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Changgong Wu
- Cardiovascular Institute, Department of Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Rong Chong
- Craniofacial Regeneration Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Raymond L Benza
- Cardiovascular Institute, Department of Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
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Crewe C, An YA, Scherer PE. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest 2017; 127:74-82. [PMID: 28045400 DOI: 10.1172/jci88883] [Citation(s) in RCA: 511] [Impact Index Per Article: 63.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential. The interactions of these processes during AT expansion reflect both a linear progression as well as feed-forward mechanisms. For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis. Therefore, the relationship between the members of this triad is complex but important for our understanding of the pathogenesis of obesity. Here we untangle some of these intricacies to highlight the contributions of inflammation, angiogenesis, and the ECM to both "healthy" and "unhealthy" AT expansion.
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Apelin/APJ system: A novel promising therapy target for pathological angiogenesis. Clin Chim Acta 2016; 466:78-84. [PMID: 28025030 DOI: 10.1016/j.cca.2016.12.023] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 12/19/2016] [Accepted: 12/22/2016] [Indexed: 12/21/2022]
Abstract
Apelin is the endogenous ligand of the G protein-coupled receptor APJ. Both Apelin and APJ receptor are widely distributed in various tissues such as heart, brain, limbs, retina and liver. Recent research indicates that the Apelin/APJ system plays an important role in pathological angiogenesis which is a progress of new blood branches developing from preexisting vessels via sprouting. In this paper, we review the important role of the Apelin/APJ system in pathological angiogenesis. The Apelin/APJ system promotes angiogenesis in myocardial infarction, ischemic stroke, critical limb ischemia, tumor, retinal angiogenesis diseases, cirrhosis, obesity, diabetes and other related diseases. Furthermore, we illustrate the detailed mechanism of pathological angiogenesis induced by the Apelin/APJ system. In conclusion, the Apelin/APJ system would be a promising therapeutic target for angiogenesis-related diseases.
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Gileles-Hillel A, Kheirandish-Gozal L, Gozal D. Biological plausibility linking sleep apnoea and metabolic dysfunction. Nat Rev Endocrinol 2016; 12:290-8. [PMID: 26939978 DOI: 10.1038/nrendo.2016.22] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Obstructive sleep apnoea (OSA) is a very common disorder that affects 10-25% of the general population. In the past two decades, OSA has emerged as a cardiometabolic risk factor in both paediatric and adult populations. OSA-induced metabolic perturbations include dyslipidaemia, atherogenesis, liver dysfunction and abnormal glucose metabolism. The mainstay of treatment for OSA is adenotonsillectomy in children and continuous positive airway pressure therapy in adults. Although these therapies are effective at resolving the sleep-disordered breathing component of OSA, they do not always produce beneficial effects on metabolic function. Thus, a deeper understanding of the underlying mechanisms by which OSA influences metabolic dysfunction might yield improved therapeutic approaches and outcomes. In this Review, we summarize the evidence obtained from animal models and studies of patients with OSA of potential mechanistic pathways linking the hallmarks of OSA (intermittent hypoxia and sleep fragmentation) with metabolic dysfunction. Special emphasis is given to adipose tissue dysfunction induced by sleep apnoea, which bears a striking resemblance to adipose dysfunction resulting from obesity. In addition, important gaps in current knowledge and promising lines of future investigation are identified.
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Affiliation(s)
- Alex Gileles-Hillel
- Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Knapp Center for Biomedical Discovery, Room 4100, 900 East 57th Street, Mailbox 4, Chicago, Illinois 60637-1470, USA
| | - Leila Kheirandish-Gozal
- Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Knapp Center for Biomedical Discovery, Room 4100, 900 East 57th Street, Mailbox 4, Chicago, Illinois 60637-1470, USA
| | - David Gozal
- Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Knapp Center for Biomedical Discovery, Room 4100, 900 East 57th Street, Mailbox 4, Chicago, Illinois 60637-1470, USA
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Luo X, Jia R, Yao Q, Xu Y, Luo Z, Luo X, Wang N. Docosahexaenoic acid attenuates adipose tissue angiogenesis and insulin resistance in high fat diet-fed middle-aged mice via a sirt1-dependent mechanism. Mol Nutr Food Res 2016; 60:871-85. [PMID: 26750093 DOI: 10.1002/mnfr.201500714] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 12/14/2015] [Accepted: 12/29/2015] [Indexed: 02/07/2023]
Abstract
SCOPE Docosahexaenoic acid (DHA; C22: 6, n-3), one of PUFAs, exerts beneficial effects on inflammatory diseases, obesity and diabetes. Angiogenesis in adipose tissue has a major role in the development of obesity and its related metabolic complications. Inhibition of angiogenesis is an emerging strategy for the novel treatment for obesity. Thus, we examined the effect of DHA on angiogenesis in adipose tissues and investigated the underlying mechanisms. METHODS AND RESULTS In high-fat diet (HFD) fed middle-aged mice, DHA inhibited the macrophage-derived inflammation and angiogenesis in adipose tissues, reduced adipocyte size and body fat composition and improved insulin sensitivity. Moreover, DHA reversed the HFD-induced reduction of Sirt1 in adipose tissues. Interestingly, the effects of DHA were attenuated by lentivirus-mediated Sirt1 knockdown with increasing expression of markers of macrophage-derived inflammation and angiogenesis, associated with impaired insulin sensitivity. CONCLUSION Overall, our findings demonstrated that DHA reduced angiogenesis of adipose tissues and attenuated insulin resistance in HFD-induced obese mice via the activation of Sirt1.
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Affiliation(s)
- Xiaoqin Luo
- Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an, P.R. China.,Department of Medicine, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, P.R. China
| | - Ru Jia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, P.R. China.,Department of Prosthodontics, Stomatological Hospital, College of Stomatology, Xi'an Jiaotong University, Xi'an, PR China
| | - Qinyu Yao
- Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Yirui Xu
- Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Zhenyu Luo
- Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Xiao Luo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, P.R. China
| | - Nanping Wang
- Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an, P.R. China
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PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-γ to increase surface FasL. Apoptosis 2015; 21:60-8. [DOI: 10.1007/s10495-015-1186-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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He L, Xu J, Chen L, Li L. Apelin/APJ signaling in hypoxia-related diseases. Clin Chim Acta 2015; 451:191-8. [PMID: 26436483 DOI: 10.1016/j.cca.2015.09.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 09/26/2015] [Accepted: 09/29/2015] [Indexed: 12/29/2022]
Abstract
The regulatory peptide apelin is the endogenous ligand for the orphan G protein-coupled receptor APJ. Apelin and APJ exist in a variety of tissues, with special status in the heart, lung and tumors. Consequently, the apelin/APJ system exerts a broad range of activities that affect multiple organ systems. Accumulating evidence indicates that the expressions of apelin and APJ are significantly augmented by hypoxia through the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway. Increased apelin promotes cellular proliferation, migration and survival, therefore regulating angiogenesis. In addition, the pre-administration of exogenous apelin is involved in the occurrence and development of hypoxia-induced pathological diseases. The purpose of this article is to review the properties of the apelin/APJ system, which is affected by hypoxic conditions, and the regulation of apelin/APJ signaling in hypoxia-associated disorders. Thus, the apelin/APJ system may be a potential therapeutic target in hypoxia-related diseases.
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Affiliation(s)
- Lu He
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, PR China
| | - Jin Xu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, PR China
| | - Linxi Chen
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, PR China.
| | - Lanfang Li
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, PR China.
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Abstract
PURPOSE OF REVIEW Because of its increasing prevalence and morbi-mortality, obesity is a major health problem. Obesity etiology includes a combination of excess dietary calories and decreased physical activity, coupled with either predisposing genetic factors or metabolic disorders such as insulin resistance. Adipose tissue secretes several metabolically important proteins known as 'adipokines' that play a major role in obesity and insulin resistance. High levels of a newly identified group of adipokines, called prokineticins, have been found in obese adipose tissues. Prokineticins are peptide hormones released principally from macrophages and reproductive organs. They act on the G protein-coupled receptors PKR1 and PKR2. This review aims to provide an overview of current knowledge of the role of prokineticins and their receptors in the development of obesity and insulin resistance. RECENT FINDINGS The principal biological effect of prokineticins in the central nervous system is the control of food intake. Nevertheless, peripheral biological effects of prokineticin are associated with increasing insulin sensitivity and suppressing the adipose tissue expansion. SUMMARY We outline the biological significance of the central and peripheral effects of prokineticins, and the potential of their receptors as targets for the treatment of obesity and insulin resistance.
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46
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Mihai AD, Schröder M. Glucose starvation and hypoxia, but not the saturated fatty acid palmitic acid or cholesterol, activate the unfolded protein response in 3T3-F442A and 3T3-L1 adipocytes. Adipocyte 2015; 4:188-202. [PMID: 26257992 DOI: 10.4161/21623945.2014.989728] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 11/08/2014] [Accepted: 11/14/2014] [Indexed: 12/26/2022] Open
Abstract
Obesity is associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in adipose tissue. In this study we identify physiological triggers of ER stress and of the UPR in adipocytes in vitro. We show that two markers of adipose tissue remodelling in obesity, glucose starvation and hypoxia, cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Both conditions induced molecular markers of the IRE1α and PERK branches of the UPR, such as splicing of XBP1 mRNA and CHOP, as well as transcription of the ER stress responsive gene BiP. Hypoxia also induced an increase in phosphorylation of the PERK substrate eIF2α. By contrast, physiological triggers of ER stress in many other cell types, such as the saturated fatty acid palmitic acid, cholesterol, or several inflammatory cytokines including TNF-α, IL-1β, and IL-6, do not cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Our data suggest that physiological changes associated with remodelling of adipose tissue in obesity, such as hypoxia and glucose starvation, are more likely physiological ER stressors of adipocytes than the lipid overload or hyperinsulinemia associated with obesity.
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47
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Buechler C, Krautbauer S, Eisinger K. Adipose tissue fibrosis. World J Diabetes 2015; 6:548-553. [PMID: 25987952 PMCID: PMC4434075 DOI: 10.4239/wjd.v6.i4.548] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 01/12/2015] [Accepted: 02/11/2015] [Indexed: 02/05/2023] Open
Abstract
The increasing prevalence of obesity causes a major interest in white adipose tissue biology. Adipose tissue cells are surrounded by extracellular matrix proteins whose composition and remodeling is of crucial importance for cell function. The expansion of adipose tissue in obesity is linked to an inappropriate supply with oxygen and hypoxia development. Subsequent activation of hypoxia inducible factor 1 (HIF-1) inhibits preadipocyte differentiation and initiates adipose tissue fibrosis. Thereby adipose tissue growth is limited and excess triglycerides are stored in ectopic tissues. Stressed adipocytes and hypoxia contribute to immune cell immigration and activation which further aggravates adipose tissue fibrosis. There is substantial evidence that adipose tissue fibrosis is linked to metabolic dysfunction, both in rodent models and in the clinical setting. Peroxisome proliferator activated receptor gamma agonists and adiponectin both reduce adipose tissue fibrosis, inflammation and insulin resistance. Current knowledge suggests that antifibrotic drugs, increasing adipose tissue oxygen supply or HIF-1 antagonists will improve adipose tissue function and thereby ameliorate metabolic diseases.
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Lai W, Tian X, Xiang Q, Chu K, Wei Y, Deng J, Zhang S, Brown J, Hong G. 11β-HSD1 modulates LPS-induced innate immune responses in adipocytes by altering expression of PTEN. Mol Endocrinol 2015; 29:558-70. [PMID: 25734515 DOI: 10.1210/me.2014-1287] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents a therapeutic target for treating hyperglycemia in type 2 diabetes. Here, we investigate the effects of 11β-HSD1 on the innate immune response of adipocytes to produce proinflammatory cytokines. The 11β-HSD1 inhibitor emodin, or 11β-HSD1-targeted small interfering RNA, dose dependently suppressed IL-6, IL-1β, and TNF-α expression in lipopolysaccharide-treated 3T3-L1 adipocytes. Inhibiting 11β-HSD1 also reduced phosphatase and tensin homologue (PTEN) expression, a negative regulator of phosphatidylinositol 3-kinase effects, whereas 1pM cortisone or dexamethasone induced IL-6 and PTEN levels. PTEN-targeted small interfering RNA decreased IL-6, IL-1β, and TNF-α without affecting 11β-HSD1 levels. Correspondingly, emodin increased phosphorylated protein kinase B (p-PKB) (Ser473) to PKB ratio but not p-PKB (Thr308) to PKB ratio. Emodin did not increase the p-PKB (Ser473) to PKB ratio when the rapamycin-insensitive companion of mTOR was depleted, further supporting the involvement of mammalian target of rapamycin complex 2 in PKB phosphorylation. Moreover, emodin suppressed phosphorylated inhibitor of κB α (p-IκBα) to IκBα ratio and reduced nuclear factor κ B subunit p50 in the nuclear fraction. In contrast, 1pM cortisone or dexamethasone decreased p-PKB (Ser473) to PKB ratio, increased p-IκBα to IκBα ratio, and increased nuclear NF-κB subunit p50. Additionally, wortmannin had similar effects on IL-6, p-PKB (Ser473) to PKB ratio, and p-IκBα to IκBα ratio as 1pM cortisone or dexamethasone. Finally, emodin treatment of streptozotocin diabetic rats on a high-fat diet reduced levels of IL-6, PTEN, Cluster of Differentiation 68, and the ratio of p-IκBα to IκBα in visceral fat, indicating that our findings in vitro may also apply to visceral fat in vivo. Together, these results suggest that inhibiting 11β-HSD1 reduces lipopolysaccharide-induced proinflammatory innate immune responses in adipocytes by down-regulating PTEN expression, leading to activation of the PI3K/PKB pathway.
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Affiliation(s)
- Wenfang Lai
- Centre of Biomedical Research and Development (W.L., X.T., Q.X., K.C., Y.W., J.D., S.Z., J.B., G.H.), Fujian University of Traditional Chinese Medicine, Minhou Shangjie, Fuzhou, 350108, China; and School of Biological Sciences (S.Z.), Faculty of Science, University of Auckland, 1142, Auckland, New Zealand
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Michailidou Z, Morton NM, Moreno Navarrete JM, West CC, Stewart KJ, Fernández-Real JM, Schofield CJ, Seckl JR, Ratcliffe PJ. Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion. Diabetes 2015; 64:733-45. [PMID: 25377876 PMCID: PMC5366882 DOI: 10.2337/db14-0233] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Prolyl hydroxylase enzymes (PHDs) sense cellular oxygen upstream of hypoxia-inducible factor (HIF) signaling, leading to HIF degradation in normoxic conditions. In this study, we demonstrate that adipose PHD2 inhibition plays a key role in the suppression of adipocyte lipolysis. Adipose Phd2 gene ablation in mice enhanced adiposity, with a parallel increase in adipose vascularization associated with reduced circulating nonesterified fatty acid levels and normal glucose homeostasis. Phd2 gene-depleted adipocytes exhibited lower basal lipolysis in normoxia and reduced β-adrenergic-stimulated lipolysis in both normoxia and hypoxia. A selective PHD inhibitor suppressed lipolysis in murine and human adipocytes in vitro and in vivo in mice. PHD2 genetic ablation and pharmacological inhibition attenuated protein levels of the key lipolytic effectors hormone-sensitive lipase and adipose triglyceride lipase (ATGL), suggesting a link between adipocyte oxygen sensing and fatty acid release. PHD2 mRNA levels correlated positively with mRNA levels of AB-hydrolase domain containing-5, an activator of ATGL, and negatively with mRNA levels of lipid droplet proteins, perilipin, and TIP47 in human subcutaneous adipose tissue. Therapeutic pseudohypoxia caused by PHD2 inhibition in adipocytes blunts lipolysis and promotes benign adipose tissue expansion and may have therapeutic applications in obesity or lipodystrophy.
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Affiliation(s)
- Zoi Michailidou
- Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, U.K. University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, U.K.
| | - Nicholas M Morton
- University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, U.K
| | - José Maria Moreno Navarrete
- CIBERobn "Pathophysiology of Obesity and Nutrition," Biomedical Research Institute of Girona (IDIBGI), Girona, Spain
| | - Christopher C West
- University of Edinburgh/MRC Centre for Regenerative Medicine, Edinburgh, U.K
| | - Kenneth J Stewart
- The Department of Plastic, Reconstructive and Burns Surgery, St. Johns Hospital, Livingston, U.K
| | - José Manuel Fernández-Real
- CIBERobn "Pathophysiology of Obesity and Nutrition," Biomedical Research Institute of Girona (IDIBGI), Girona, Spain
| | | | - Jonathan R Seckl
- University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, U.K
| | - Peter J Ratcliffe
- Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, U.K
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PPARγ activation but not PPARγ haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors. Cardiovasc Diabetol 2014; 13:150. [PMID: 25361524 PMCID: PMC4233236 DOI: 10.1186/s12933-014-0150-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 10/20/2014] [Indexed: 12/14/2022] Open
Abstract
Background Peroxisome proliferator-activated receptor-γ (PPARγ) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPARγ on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs). Methods PACs were isolated from bone marrow of 10–12 weeks old, wild type, db/db and PPARγ heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 μmol/L) or GW9662 (10 μmol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model. Results ECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPARγ activator). Correction of diabetes by administration of rosiglitazone in vivo did not improve angiogenic potential of isolated PACs or ECs. In a hind limb ischemia model we demonstrated that local injection of conditioned media harvested from wild type PACs improved the blood flow restoration in db/db mice, confirming the importance of paracrine action of the bone marrow-derived cells. Transcriptome analysis showed an upregulation of prooxidative and proinflammatory pathways, and downregulation of several proangiogenic genes in db/db PACs. Interestingly, db/db PACs had also a decreased level of PPARγ and changed expression of PPARγ-regulated genes. Using normoglycemic PPARγ+/− mice we demonstrated that reduced expression of PPARγ does not influence neovascularization either in wound healing or in hind limb ischemia models. Conclusions In summary, activation of PPARγ by rosiglitazone improves angiogenic potential of diabetic ECs and PACs, but decreased expression of PPARγ in diabetes does not impair angiogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12933-014-0150-7) contains supplementary material, which is available to authorized users.
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