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Salyer LG, Wang Y, Ma X, Foryst-Ludwig A, Kintscher U, Chennappan S, Kontaridis MI, McKinsey TA. Modulating the Secretome of Fat to Treat Heart Failure. Circ Res 2025; 136:1363-1381. [PMID: 40403114 DOI: 10.1161/circresaha.125.325593] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/24/2025]
Abstract
Heart failure afflicts >6 million individuals in the United States alone and is associated with significant mortality (≈40% within 5 years of diagnosis) and cost (estimated to exceed $70 billion in the United States by 2030). Obesity is a major risk factor for the development of heart failure. The contribution of excess adipose tissue to heart failure pathogenesis is multifactorial. For example, adipose tissue-driven inflammation contributes to the development of other cardiometabolic comorbidities, such as hypertension, leading to left ventricular pressure overload and adverse remodeling of the heart. Adipose tissue also functions as an endocrine organ, and altered secretion of proteins, lipid mediators, metabolites, and small extracellular vesicles (collectively referred to as the secretome) from dysfunctional fat can lead to cardiac inflammation and oxidative stress, which drive changes in structure and function of the heart. In this review, we begin with an overview of current therapies for obesity and what is known about how they influence the heart. Then we focus on mechanisms by which fat communicates with the heart via secreted factors and highlight druggable nodes in this circuit that could be exploited to develop next-generation therapies for heart failure.
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Affiliation(s)
- Lorien G Salyer
- Division of Cardiology, Department of Medicine (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
- Consortium for Fibrosis Research & Translation (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Yajing Wang
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL (Y.W.)
| | - Xinliang Ma
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (X.M.)
| | - Anna Foryst-Ludwig
- Institute of Pharmacology, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany (A.F.-L., U.K.)
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany (A.F.-L., U.K.)
| | - Ulrich Kintscher
- Institute of Pharmacology, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany (A.F.-L., U.K.)
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany (A.F.-L., U.K.)
| | - Saravanakkumar Chennappan
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY (S.C., M.I.K.)
| | - Maria I Kontaridis
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY (S.C., M.I.K.)
- Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (M.I.K.)
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA (M.I.K.)
| | - Timothy A McKinsey
- Division of Cardiology, Department of Medicine (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
- Consortium for Fibrosis Research & Translation (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
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Tanwar VS, Reddy MA, Dey S, Malek V, Lanting L, Chen Z, Ganguly R, Natarajan R. Palmitic acid alters enhancers/super-enhancers near inflammatory and efferocytosis-associated genes in human monocytes. J Lipid Res 2025; 66:100774. [PMID: 40068774 PMCID: PMC12002881 DOI: 10.1016/j.jlr.2025.100774] [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: 12/07/2024] [Revised: 02/20/2025] [Accepted: 03/07/2025] [Indexed: 04/07/2025] Open
Abstract
Free fatty acids like palmitic acid (PA) are elevated in obesity and diabetes and dysregulate monocyte and macrophage functions, contributing to enhanced inflammation in these cardiometabolic diseases. Epigenetic mechanisms regulating enhancer functions play key roles in inflammatory gene expression, but their role in PA-induced monocyte/macrophage dysfunction is unknown. We found that PA treatment altered the epigenetic landscape of enhancers and super-enhancers (SEs) in human monocytes. Integration with RNA-seq data revealed that PA-induced enhancers/SEs correlated with PA-increased expression of inflammatory and immune response genes, while PA-inhibited enhancers correlated with downregulation of phagocytosis and efferocytosis genes. These genes were similarly regulated in macrophages from mouse models of diabetes and accelerated atherosclerosis, human atherosclerosis, and infectious agents. PA-regulated enhancers/SEs harbored SNPs associated with diabetes, obesity, and body mass index indicating disease relevance. We verified increased chromatin interactions between PA-regulated enhancers/SEs and inflammatory gene promoters and reduced interactions at efferocytosis genes. PA-induced gene expression was reduced by inhibitors of BRD4, and NF-κB. PA treatment inhibited phagocytosis and efferocytosis in human macrophages. Together, our findings demonstrate that PA-induced enhancer dynamics at key monocyte/macrophage enhancers/SEs regulate inflammatory and immune genes and responses. Targeting these PA-regulated epigenetic changes could provide novel therapeutic opportunities for cardiometabolic disorders.
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Affiliation(s)
- Vinay Singh Tanwar
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Marpadga A Reddy
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Suchismita Dey
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Vajir Malek
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Linda Lanting
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Zhuo Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Rituparna Ganguly
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Hu S, Kang H, Bae M, Kim MB, Jang H, Corvino O, Pham TX, Lee Y, Smyth JA, Park YK, Lee JY. Histone Deacetylase 9 Deletion Inhibits Hepatic Steatosis and Adipose Tissue Inflammation in Male Diet-Induced Obese Mice. J Gastroenterol Hepatol 2025; 40:741-749. [PMID: 39730208 PMCID: PMC11875955 DOI: 10.1111/jgh.16856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 11/26/2024] [Accepted: 12/11/2024] [Indexed: 12/29/2024]
Abstract
AIM The goal of this study was to determine the role of histone deacetylase 9 (HDAC9) in the development of diet-induced metabolic dysfunction-associated steatohepatitis (MASH) and white adipose tissue (WAT) dysfunctions. METHODS We fed male and female mice with global Hdac9 knockout (KO) and their wild-type (WT) littermates an obesogenic high-fat/high-sucrose/high-cholesterol (35%/34%/2%, w/w) diet for 20 weeks. RESULTS Hdac9 deletion markedly inhibited body weight gain and liver steatosis with lower liver weight and triglyceride content than WT in male mice but not females. Consistently, hepatic expression of genes crucial for de novo lipogenesis was markedly suppressed only in male, but not female, Hdac9 KO mice. However, Hdac9 deletion had a minimal effect on hepatic inflammation and fibrosis. In WAT, Hdac9 KO showed less adipocyte hypertrophy, inflammation, and fibrosis in male mice compared with WT. In addition, indirect calorimetry demonstrated that male Hdac9 KO mice had significantly higher metabolic rates, respiratory exchange ratios, and energy expenditure without altering physical activities than WT, which was not observed in female mice. CONCLUSIONS Our findings indicate that global deletion of Hdac9 prevented the development of obesity, hepatic steatosis, and WAT inflammation and fibrosis in male mice with diet-induced obesity and MASH, suggesting that a sex-dependent role of HDAC9 may exist in the pathways mentioned above.
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Affiliation(s)
- Siqi Hu
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
- Department of Food and Nutrition, Keimyung University, Daegu, South Korea
| | - Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
- Department of Food and Nutrition, Yonsei University, Seoul, South Korea
| | - Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Hyungryun Jang
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Olivia Corvino
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Tho X Pham
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Yoojin Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Joan A Smyth
- Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
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Yang J, Li G, Wang S, He M, Dong S, Wang T, Shi B, Rensen PCN, Wang Y. Butyrate Prevents Obesity Accompanied by HDAC9-Mediated Browning of White Adipose Tissue. Biomedicines 2025; 13:260. [PMID: 40002674 PMCID: PMC11852213 DOI: 10.3390/biomedicines13020260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The objective of this study was to investigate butyrate-induced thermogenesis in white adipose tissue and its underlying mechanism. METHODS We studied the effects of butyrate on diet-induced obesity in the humanized APOE*3-Leiden.CETP transgenic mouse model and explored factors related to white adipose browning. Specifically, mice were challenged with a high-fat diet supplemented with butyrate. Adiposity was measured to assess obesity development. Energy metabolism was detected using an indirect calorimetry system. RNA-seq analysis was conducted to analyze the transcription landscape of WAT and responsible targets. Furthermore, the revealed molecular mechanism was verified in vitro. RESULTS Butyrate alleviated high-fat diet-induced obesity and promoted energy expenditure accompanied by brown adipose tissue activation and WAT browning. Mechanistically, RNA-seq analysis revealed that butyrate downregulated HDAC9 in WAT. Additionally, butyrate decreased HDAC9 while increasing thermogenesis in vitro. Inhibition of HDAC9 with TMP269 promoted thermogenic gene expression, mimicking the effects of butyrate. CONCLUSIONS Butyrate protects against diet-induced obesity accompanied by decreasing the expression of HDAC9 in white adipose tissue and inducing browning. This study reveals a new mechanism whereby butyrate activates adaptive thermogenesis and provides new insights for the development of weight-loss drugs targeting adipose HDAC9.
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Affiliation(s)
- Jing Yang
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Guoli Li
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Shan Wang
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Mingqian He
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Sijing Dong
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Ting Wang
- Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital, Xi’an 710061, China
| | - Binyin Shi
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Patrick C. N. Rensen
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, P.O. Box 9600, 2300 Leiden, The Netherlands
| | - Yanan Wang
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, P.O. Box 9600, 2300 Leiden, The Netherlands
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Li Y, Han Q, Liu Y, Yin J, Ma J. Role of the histone deacetylase family in lipid metabolism: Structural specificity and functional diversity. Pharmacol Res 2024; 210:107493. [PMID: 39491635 DOI: 10.1016/j.phrs.2024.107493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/23/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
Lipids play crucial roles in signal transduction. Lipid metabolism is associated with several transcriptional regulators, including peroxisome proliferator activated receptor γ, sterol regulatory element-binding protein 1, and acetyl-CoA carboxylase. In recent years, increasing evidence has suggested that members of the histone deacetylase (HDAC) family play key roles in lipid metabolism. However, the mechanisms by which each member of this family regulates lipid metabolism remain unclear. This review discusses the latest research on the roles played by HDACs in fat metabolism. The role of HDACs in obesity, diabetes, and atherosclerosis has also been discussed. In addition, the interaction of HDACs with the gut microbiome and circadian rhythm has been reviewed, and the future development trend in HDACs has been predicted, which may potentiate therapeutic application of targeted HDACs in related metabolic diseases.
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Affiliation(s)
- Yunxia Li
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China
| | - Qi Han
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China
| | - Yuxin Liu
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China
| | - Jie Yin
- College of Animal Science and Technology, Hunan Agriculture University, Changsha 410128, China.
| | - Jie Ma
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China.
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Huang X, Chen J, Li H, Cai Y, Liu L, Dong Q, Li Y, Ren Y, Xiang W, He X. LncRNA SNHG12 suppresses adipocyte inflammation and insulin resistance by regulating the HDAC9/Nrf2 axis. FASEB J 2024; 38:e23794. [PMID: 38967258 DOI: 10.1096/fj.202400236rr] [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: 01/30/2024] [Revised: 06/12/2024] [Accepted: 06/24/2024] [Indexed: 07/06/2024]
Abstract
Obesity is often associated with low-grade inflammation. The incidence of obesity has increased annually worldwide, which seriously affects human health. A previous study indicated that long noncoding RNA SNHG12 was downregulated in obesity. Nevertheless, the role of SNHG12 in obesity remains to be elucidated. In this study, qRT-PCR, western blot, and ELISA were utilized to examine the gene and protein expression. Flow cytometry was employed to investigate the M2 macrophage markers. RNA pull-down assay and RIP were utilized to confirm the interactions of SNHG12, hnRNPA1, and HDAC9. Eventually, a high-fat diet-fed mouse model was established for in vivo studies. SNHG12 overexpression suppressed adipocyte inflammation and insulin resistance and promoted M2 polarization of macrophages that was caused by TNF-α treatment. SNHG12 interacted with hnRNPA1 to downregulate HDAC9 expression, which activated the Nrf2 signaling pathway. HDAC9 overexpression reversed the effect of SNHG12 overexpression on inflammatory response, insulin resistance, and M2 phenotype polarization. Overexpression of SNHG12 improved high-fat diet-fed mouse tissue inflammation. This study revealed the protective effect of SNHG12 against adipocyte inflammation and insulin resistance. This result further provides a new therapeutic target for preventing inflammation and insulin resistance in obesity.
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Affiliation(s)
- Xiaoyan Huang
- Department of Genetics, Metabolism and Endocrinology, Hainan Women and Children's Medical Center, Haikou, China
| | - Jixiong Chen
- Department of Medical Care Center, Hainan Provincial People's Hospital, Haikou, China
| | - Haidan Li
- Department of Genetics, Metabolism and Endocrinology, Hainan Women and Children's Medical Center, Haikou, China
| | - Yuhua Cai
- Department of Genetics, Metabolism and Endocrinology, Hainan Women and Children's Medical Center, Haikou, China
| | - Li Liu
- Department of Genetics, Metabolism and Endocrinology, Hainan Women and Children's Medical Center, Haikou, China
| | - Qi Dong
- Department of Genetics, Metabolism and Endocrinology, Hainan Women and Children's Medical Center, Haikou, China
| | - Yan Li
- Department of Genetics, Metabolism and Endocrinology, Hainan Women and Children's Medical Center, Haikou, China
| | - Yi Ren
- Department of Pediatrics, Haikou Hospital of the Maternal and Child Health, Haikou, China
| | - Wei Xiang
- Hainan Women and Children's Medical Center, Haikou, China
| | - Xiaojie He
- Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
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Kumar KK, Aburawi EH, Ljubisavljevic M, Leow MKS, Feng X, Ansari SA, Emerald BS. Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues. Clin Epigenetics 2024; 16:78. [PMID: 38862980 PMCID: PMC11167878 DOI: 10.1186/s13148-024-01692-0] [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: 02/27/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024] Open
Abstract
Diabetes mellitus is a chronic disease that impairs metabolism, and its prevalence has reached an epidemic proportion globally. Most people affected are with type 2 diabetes mellitus (T2DM), which is caused by a decline in the numbers or functioning of pancreatic endocrine islet cells, specifically the β-cells that release insulin in sufficient quantity to overcome any insulin resistance of the metabolic tissues. Genetic and epigenetic factors have been implicated as the main contributors to the T2DM. Epigenetic modifiers, histone deacetylases (HDACs), are enzymes that remove acetyl groups from histones and play an important role in a variety of molecular processes, including pancreatic cell destiny, insulin release, insulin production, insulin signalling, and glucose metabolism. HDACs also govern other regulatory processes related to diabetes, such as oxidative stress, inflammation, apoptosis, and fibrosis, revealed by network and functional analysis. This review explains the current understanding of the function of HDACs in diabetic pathophysiology, the inhibitory role of various HDAC inhibitors (HDACi), and their functional importance as biomarkers and possible therapeutic targets for T2DM. While their role in T2DM is still emerging, a better understanding of the role of HDACi may be relevant in improving insulin sensitivity, protecting β-cells and reducing T2DM-associated complications, among others.
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Affiliation(s)
- Kukkala Kiran Kumar
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 15551, Al Ain, Abu Dhabi, United Arab Emirates
| | - Elhadi Husein Aburawi
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Milos Ljubisavljevic
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
- Duke-NUS Medical School, Cardiovascular and Metabolic Disorders Program, Singapore, Singapore
| | - Melvin Khee Shing Leow
- LKC School of Medicine, Nanyang Technological University, Singapore, Singapore
- Dept of Endocrinology, Tan Tock Seng Hospital, Singapore, Singapore
- Duke-NUS Medical School, Cardiovascular and Metabolic Disorders Program, Singapore, Singapore
| | - Xu Feng
- Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore, Singapore
| | - Suraiya Anjum Ansari
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates
- ASPIRE Precision Medicine Research Institute, Abu Dhabi, United Arab Emirates
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 15551, Al Ain, Abu Dhabi, United Arab Emirates.
- Zayed Center for Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates.
- ASPIRE Precision Medicine Research Institute, Abu Dhabi, United Arab Emirates.
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Šimon M, Mikec Š, Atanur SS, Konc J, Morton NM, Horvat S, Kunej T. Whole genome sequencing of mouse lines divergently selected for fatness (FLI) and leanness (FHI) revealed several genetic variants as candidates for novel obesity genes. Genes Genomics 2024; 46:557-575. [PMID: 38483771 PMCID: PMC11024027 DOI: 10.1007/s13258-024-01507-9] [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: 05/04/2023] [Accepted: 02/25/2024] [Indexed: 04/18/2024]
Abstract
BACKGROUND Analysing genomes of animal model organisms is widely used for understanding the genetic basis of complex traits and diseases, such as obesity, for which only a few mouse models exist, however, without their lean counterparts. OBJECTIVE To analyse genetic differences in the unique mouse models of polygenic obesity (Fat line) and leanness (Lean line) originating from the same base population and established by divergent selection over more than 60 generations. METHODS Genetic variability was analysed using WGS. Variants were identified with GATK and annotated with Ensembl VEP. g.Profiler, WebGestalt, and KEGG were used for GO and pathway enrichment analysis. miRNA seed regions were obtained with miRPathDB 2.0, LncRRIsearch was used to predict targets of identified lncRNAs, and genes influencing adipose tissue amount were searched using the IMPC database. RESULTS WGS analysis revealed 6.3 million SNPs, 1.3 million were new. Thousands of potentially impactful SNPs were identified, including within 24 genes related to adipose tissue amount. SNP density was highest in pseudogenes and regulatory RNAs. The Lean line carries SNP rs248726381 in the seed region of mmu-miR-3086-3p, which may affect fatty acid metabolism. KEGG analysis showed deleterious missense variants in immune response and diabetes genes, with food perception pathways being most enriched. Gene prioritisation considering SNP GERP scores, variant consequences, and allele comparison with other mouse lines identified seven novel obesity candidate genes: 4930441H08Rik, Aff3, Fam237b, Gm36633, Pced1a, Tecrl, and Zfp536. CONCLUSION WGS revealed many genetic differences between the lines that accumulated over the selection period, including variants with potential negative impacts on gene function. Given the increasing availability of mouse strains and genetic polymorphism catalogues, the study is a valuable resource for researchers to study obesity.
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Affiliation(s)
- Martin Šimon
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia.
| | - Špela Mikec
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia
| | - Santosh S Atanur
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, SW7 2AZ, UK
- Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Janez Konc
- Laboratory for Molecular Modeling, National Institute of Chemistry, Ljubljana, 1000, Slovenia
| | - Nicholas M Morton
- The Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Simon Horvat
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia
| | - Tanja Kunej
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia.
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Veerapaneni P, Goo B, Ahmadieh S, Shi H, Kim DS, Ogbi M, Cave S, Chouhaita R, Cyriac N, Fulton DJ, Verin AD, Chen W, Lei Y, Lu XY, Kim HW, Weintraub NL. Transgenic Overexpression of HDAC9 Promotes Adipocyte Hypertrophy, Insulin Resistance and Hepatic Steatosis in Aging Mice. Biomolecules 2024; 14:494. [PMID: 38672510 PMCID: PMC11048560 DOI: 10.3390/biom14040494] [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: 02/13/2024] [Revised: 04/05/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
Histone deacetylase (HDAC) 9 is a negative regulator of adipogenic differentiation, which is required for maintenance of healthy adipose tissues. We reported that HDAC9 expression is upregulated in adipose tissues during obesity, in conjunction with impaired adipogenic differentiation, adipocyte hypertrophy, insulin resistance, and hepatic steatosis, all of which were alleviated by global genetic deletion of Hdac9. Here, we developed a novel transgenic (TG) mouse model to test whether overexpression of Hdac9 is sufficient to induce adipocyte hypertrophy, insulin resistance, and hepatic steatosis in the absence of obesity. HDAC9 TG mice gained less body weight than wild-type (WT) mice when fed a standard laboratory diet for up to 40 weeks, which was attributed to reduced fat mass (primarily inguinal adipose tissue). There was no difference in insulin sensitivity or glucose tolerance in 18-week-old WT and HDAC9 TG mice; however, at 40 weeks of age, HDAC9 TG mice exhibited impaired insulin sensitivity and glucose intolerance. Tissue histology demonstrated adipocyte hypertrophy, along with reduced numbers of mature adipocytes and stromovascular cells, in the HDAC9 TG mouse adipose tissue. Moreover, increased lipids were detected in the livers of aging HDAC9 TG mice, as evaluated by oil red O staining. In conclusion, the experimental aging HDAC9 TG mice developed adipocyte hypertrophy, insulin resistance, and hepatic steatosis, independent of obesity. This novel mouse model may be useful in the investigation of the impact of Hdac9 overexpression associated with metabolic and aging-related diseases.
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Affiliation(s)
- Praneet Veerapaneni
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - Brandee Goo
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - Samah Ahmadieh
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - Hong Shi
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
- Department of Medicine, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA
| | - David S. Kim
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - Mourad Ogbi
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - Stephen Cave
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - Ronnie Chouhaita
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - Nicole Cyriac
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
| | - David J. Fulton
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA
| | - Alexander D. Verin
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
- Department of Medicine, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA
| | - Weiqin Chen
- Department of Physiology, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA;
| | - Yun Lei
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (Y.L.); (X.-Y.L.)
| | - Xin-Yun Lu
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (Y.L.); (X.-Y.L.)
| | - Ha Won Kim
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
- Department of Medicine, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA
| | - Neal L. Weintraub
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA; (P.V.); (B.G.); (S.A.); (H.S.); (D.S.K.); (M.O.); (S.C.); (R.C.); (N.C.); (D.J.F.); (A.D.V.); (H.W.K.)
- Department of Medicine, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd, Augusta, GA 30912, USA
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10
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Liu SS, Fang X, Wen X, Liu JS, Alip M, Sun T, Wang YY, Chen HW. How mesenchymal stem cells transform into adipocytes: Overview of the current understanding of adipogenic differentiation. World J Stem Cells 2024; 16:245-256. [PMID: 38577237 PMCID: PMC10989283 DOI: 10.4252/wjsc.v16.i3.245] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/15/2024] [Accepted: 02/18/2024] [Indexed: 03/25/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are stem/progenitor cells capable of self-renewal and differentiation into osteoblasts, chondrocytes and adipocytes. The transformation of multipotent MSCs to adipocytes mainly involves two subsequent steps from MSCs to preadipocytes and further preadipocytes into adipocytes, in which the process MSCs are precisely controlled to commit to the adipogenic lineage and then mature into adipocytes. Previous studies have shown that the master transcription factors C/enhancer-binding protein alpha and peroxisome proliferation activator receptor gamma play vital roles in adipogenesis. However, the mechanism underlying the adipogenic differentiation of MSCs is not fully understood. Here, the current knowledge of adipogenic differentiation in MSCs is reviewed, focusing on signaling pathways, noncoding RNAs and epigenetic effects on DNA methylation and acetylation during MSC differentiation. Finally, the relationship between maladipogenic differentiation and diseases is briefly discussed. We hope that this review can broaden and deepen our understanding of how MSCs turn into adipocytes.
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Affiliation(s)
- Shan-Shan Liu
- Department of Reumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Xiang Fang
- Department of Emergency, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Xin Wen
- Department of Reumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Ji-Shan Liu
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| | - Miribangvl Alip
- Department of Reumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Tian Sun
- Department of Reumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Yuan-Yuan Wang
- Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu 233000, Anhui Province, China
| | - Hong-Wei Chen
- Department of Reumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China.
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11
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Liu J, Meng L, Liu Z, Lu M, Wang R. Identification of HDAC9 and ARRDC4 as potential biomarkers and targets for treatment of type 2 diabetes. Sci Rep 2024; 14:7083. [PMID: 38528189 PMCID: PMC10963792 DOI: 10.1038/s41598-024-57794-5] [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: 03/24/2023] [Accepted: 03/21/2024] [Indexed: 03/27/2024] Open
Abstract
We aimed to identify the key potential insulin resistance (IR)-related genes and investigate their correlation with immune cell infiltration in type 2 diabetes (T2D). The GSE78721 dataset (68 diabetic patients and 62 controls) was downloaded from the Gene Expression Omnibus database and utilized for single-sample gene set enrichment analysis. IR-related genes were obtained from the Comparative Toxicology Genetics Database, and the final IR-differentially expressed genes (DEGs) were screened by intersecting with the DEGs obtained from the GSE78721 datasets. Functional enrichment analysis was performed, and the networks of the target gene with microRNA, transcription factor, and drug were constructed. Hub genes were identified based on a protein-protein interaction network. Least absolute shrinkage and selection operator regression and Random Forest and Boruta analysis were combined to screen diagnostic biomarkers in T2D, which were validated using the GSE76894 (19 diabetic patients and 84 controls) and GSE9006 (12 diabetic patients and 24 controls) datasets. Quantitative real-time polymerase chain reaction was performed to validate the biomarker expression in IR mice and control mice. In addition, infiltration of immune cells in T2D and their correlation with the identified markers were computed using CIBERSORT. We identified differential immune gene set regulatory T-cells in the GSE78721 dataset, and T2D samples were assigned into three clusters based on immune infiltration. A total of 2094 IR-DEGs were primarily enriched in response to endoplasmic reticulum stress. Importantly, HDAC9 and ARRDC4 were identified as markers of T2D and associated with different levels of immune cell infiltration. HDAC9 mRNA level were higher in the IR mice than in control mice, while ARRDC4 showed the opposite trend. In summary, we discovered potential vital biomarkers that contribute to immune cell infiltration associated with IR, which offers a new sight of immunotherapy for T2D.
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Affiliation(s)
- Jing Liu
- Endocrinology Department, The Second Hospital of Hebei Medical University, No.215 Heping West Road, Shijiazhuang, 050000, People's Republic of China
| | - Lingzhen Meng
- General Medical Department, The Fourth Hospital of Hebei Medical University, No.12 Jiankang Road, Shijiazhuang, 050000, People's Republic of China
| | - Zhihong Liu
- Endocrinology Department, The Second Hospital of Hebei Medical University, No.215 Heping West Road, Shijiazhuang, 050000, People's Republic of China.
| | - Ming Lu
- Medical Department, The Second Hospital of Hebei Medical University, No.215 Heping West Road, Shijiazhuang, 050000, People's Republic of China
| | - Ruiying Wang
- Endocrinology Department, The Second Hospital of Hebei Medical University, No.215 Heping West Road, Shijiazhuang, 050000, People's Republic of China
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12
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Liu R, Li L, Wang Z, Zhu J, Ji Y. Acetylated Histone Modifications: Intersection of Diabetes and Atherosclerosis. J Cardiovasc Pharmacol 2024; 83:207-219. [PMID: 37989137 DOI: 10.1097/fjc.0000000000001516] [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: 03/15/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
ABSTRACT Worldwide, type 2 diabetes is predominant form of diabetes, and it is mainly affected by the environment. Furthermore, the offspring of patients with type 2 diabetes and metabolic disorder syndrome may have a higher risk of diabetes and cardiovascular disease, which indicates that the environmental impact on diabetes prevalence can be transmitted across generations. In the process of diabetes onset and intergenerational transmission, the genetic structure of the individual is not directly changed but is regulated by epigenetics. In this process, genes or histones are modified, resulting in selective expression of proteins. This modification will affect not only the onset of diabetes but also the related onset of atherosclerosis. Acetylation and deacetylation may be important regulatory factors for the above lesions. Therefore, in this review, based on the whole process of atherosclerosis evolution, we explored the possible existence of acetylation/deacetylation caused by diabetes. However, because of the lack of atherosclerosis-related acetylation studies directly based on diabetic models, we also used a small number of experiments involving nondiabetic models of related molecular mechanisms.
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Affiliation(s)
| | | | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China; and
| | - Jie Zhu
- Department of Cardiology, The Lu'an Hospital Affiliated to Anhui Medical University, The Lu' an People's Hospital, Lu'an, China
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13
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Yang H, Li C, Che M, Liang J, Tian X, Yang G, Sun C. HDAC11 deficiency resists obesity by converting adipose-derived stem cells into brown adipocyte-like cells. Int J Biol Macromol 2024; 258:128852. [PMID: 38110164 DOI: 10.1016/j.ijbiomac.2023.128852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 11/17/2023] [Accepted: 12/14/2023] [Indexed: 12/20/2023]
Abstract
Obesity, with complications such as type 2 diabetes, dyslipidemia, and even cancer, is rampant worldwide. Histone deacetylases (HDACs) have been extensively studied as key players in the epigenetic regulation of cellular metabolism. However, the function of HDAC11 has long been focused on the immune and nervous systems and cancer development, and its potential role in obesity has been poorly studied. We found that the expression of HDAC11 was highly upregulated in the white adipose tissue (WAT) of obese mice and was closely related to the progression of obesity. Knockdown of HDAC11 by lentiviral injection in high-fat diet-fed mice attenuated the development of obesity. Furthermore, knockdown of HDAC11 ameliorated WAT hypertrophy and induced WAT browning. At the cellular level, silencing of HDAC11 promoted the differentiation of adipose-derived stem cells (ADSCs) into brown adipocyte-like cells and inhibited the proliferation of ADSCs. More interestingly, HDAC11 expression was elevated in ADSCs isolated from obese mice, and silencing of HDAC11 facilitated the spontaneous differentiation of ADSCs into mesoderm, which is the source of adipocytes. This also superficially and effectively demonstrates the exciting prospect of HDAC11 silencing in obesity research and treatment, as a valve for "energy saving and flow reduction".
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Affiliation(s)
- Hong Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chaowei Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Meng Che
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Juntong Liang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xin Tian
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Gongshe Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Chao Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
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Das T, Khatun S, Jha T, Gayen S. HDAC9 as a Privileged Target: Reviewing its Role in Different Diseases and Structure-activity Relationships (SARs) of its Inhibitors. Mini Rev Med Chem 2024; 24:767-784. [PMID: 37818566 DOI: 10.2174/0113895575267301230919165827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/17/2023] [Accepted: 08/11/2023] [Indexed: 10/12/2023]
Abstract
HDAC9 is a histone deacetylase enzyme belonging to the class IIa of HDACs which catalyses histone deacetylation. HDAC9 inhibit cell proliferation by repairing DNA, arresting the cell cycle, inducing apoptosis, and altering genetic expression. HDAC9 plays a significant part in human physiological system and are involved in various type of diseases like cancer, diabetes, atherosclerosis and CVD, autoimmune response, inflammatory disease, osteoporosis and liver fibrosis. This review discusses the role of HDAC9 in different diseases and structure-activity relationships (SARs) of various hydroxamate and non-hydroxamate-based inhibitors. SAR of compounds containing several scaffolds have been discussed in detail. Moreover, structural requirements regarding the various components of HDAC9 inhibitor (cap group, linker and zinc-binding group) has been highlighted in this review. Though, HDAC9 is a promising target for the treatment of a number of diseases including cancer, a very few research are available. Thus, this review may provide useful information for designing novel HDAC9 inhibitors to fight against different diseases in the future.
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Affiliation(s)
- Totan Das
- Department of Pharmaceutical Technology, Laboratory of Drug Design and Discovery, Jadavpur University, Kolkata, 700032, India
| | - Samima Khatun
- Department of Pharmaceutical Technology, Laboratory of Drug Design and Discovery, Jadavpur University, Kolkata, 700032, India
| | - Tarun Jha
- Department of Pharmaceutical Technology, Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Jadavpur University, Kolkata, 700032, India
| | - Shovanlal Gayen
- Department of Pharmaceutical Technology, Laboratory of Drug Design and Discovery, Jadavpur University, Kolkata, 700032, India
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15
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Ahmadieh S, Goo B, Zarzour A, Kim D, Shi H, Veerapaneni P, Chouhaita R, Yiew NK, Gonzalez CD, Chakravartty A, Pennoyer J, Hassan N, Benson TW, Ogbi M, Fulton DJ, Lee R, Rice RD, Hilton LR, Lei Y, Lu XY, Chen W, Kim HW, Weintraub NL. Impact of housing temperature on adipose tissue HDAC9 expression and adipogenic differentiation in high fat-fed mice. Obesity (Silver Spring) 2024; 32:107-119. [PMID: 37869960 PMCID: PMC10840750 DOI: 10.1002/oby.23924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 08/15/2023] [Accepted: 08/22/2023] [Indexed: 10/24/2023]
Abstract
OBJECTIVE Impaired adipogenic differentiation exacerbates metabolic disease in obesity. This study reported that high-fat diet (HFD)-fed mice housed at thermoneutrality exhibited impaired adipogenic differentiation, attributed to increased expression of histone deacetylase 9 (HDAC9). However, the impact of HFD on adipogenic differentiation is reportedly variable, possibly reflecting divergent environmental conditions such as housing temperature. METHODS C57BL/6J (wild-type [WT]) mice were housed at either thermoneutral (28-30°C) or ambient (20-22°C) temperature and fed HFD or chow diet (CD) for 12 weeks. For acute exposure experiments, WT or transient receptor potential cation channel subfamily M member 8 (TRPM8) knockout mice housed under thermoneutrality were acutely exposed to ambient temperature for 6 to 24 h. RESULTS WT mice fed HFD and housed at thermoneutrality, compared with ambient temperature, gained more weight despite reduced food intake. They likewise exhibited increased inguinal adipose tissue HDAC9 expression and reduced adipogenic differentiation in vitro and in vivo compared with CD-fed mice. Conversely, HFD-fed mice housed at ambient temperature exhibited minimal change in adipose HDAC9 expression or adipogenic differentiation. Acute exposure of WT mice to ambient temperature reduced adipose HDAC9 expression independent of sympathetic β-adrenergic signaling via a TRPM8-dependent mechanism. CONCLUSIONS Adipose HDAC9 expression is temperature sensitive, regulating adipogenic differentiation in HFD-fed mice housed under thermoneutrality.
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Affiliation(s)
- Samah Ahmadieh
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Brandee Goo
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Abdalrahman Zarzour
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - David Kim
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Hong Shi
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Praneet Veerapaneni
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Ronnie Chouhaita
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Nicole K.H. Yiew
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
- Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA
| | - Carla Dominguez Gonzalez
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Akash Chakravartty
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - James Pennoyer
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Nazeera Hassan
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Tyler W. Benson
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Mourad Ogbi
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - David J. Fulton
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
- Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA
| | - Richard Lee
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA
| | - Robert D. Rice
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA
| | - Lisa R. Hilton
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA
| | - Yun Lei
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA
| | - Xin-Yun Lu
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA
| | - Weiqin Chen
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA
| | - Ha Won Kim
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
| | - Neal L. Weintraub
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA
- Department of Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA
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16
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Wang X, Li N, Zheng M, Yu Y, Zhang S. Acetylation and deacetylation of histone in adipocyte differentiation and the potential significance in cancer. Transl Oncol 2024; 39:101815. [PMID: 37935080 PMCID: PMC10654249 DOI: 10.1016/j.tranon.2023.101815] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/17/2023] [Accepted: 10/22/2023] [Indexed: 11/09/2023] Open
Abstract
Adipocytes are derived from pluripotent mesenchymal stem cells and can develop into several cell types including adipocytes, myocytes, chondrocytes, and osteocytes. Adipocyte differentiation is regulated by a variety of transcription factors and signaling pathways. Various epigenetic factors, particularly histone modifications, play key roles in adipocyte differentiation and have indispensable functions in altering chromatin conformation. Histone acetylases and deacetylases participate in the regulation of protein acetylation, mediate transcriptional and post-translational modifications, and directly acetylate or deacetylate various transcription factors and regulatory proteins. The adipocyte differentiation of stem cells plays a key role in various metabolic diseases. Cancer stem cells(CSCs) play an important function in cancer metastasis, recurrence, and drug resistance, and have the characteristics of stem cells. They are expressed in various cell lineages, including adipocytes. Recent studies have shown that cancer stem cells that undergo epithelial-mesenchymal transformation can undergo adipocytic differentiation, thereby reducing the degree of malignancy. This opens up new possibilities for cancer treatment. This review summarizes the regulation of acetylation during adipocyte differentiation, involving the functions of histone acetylating and deacetylating enzymes as well as non-histone acetylation modifications. Mechanistic studies on adipogenesis and acetylation during the differentiation of cancer cells into a benign cell phenotype may help identify new targets for cancer treatment.
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Affiliation(s)
- Xiaorui Wang
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin 300121, China; Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Na Li
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin 300121, China; Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin 300121, China
| | - Yongjun Yu
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin 300121, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin 300121, China.
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17
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Zhou R, Cao Y, Xiang Y, Fang P, Shang W. Emerging roles of histone deacetylases in adaptive thermogenesis. Front Endocrinol (Lausanne) 2023; 14:1124408. [PMID: 36875455 PMCID: PMC9978507 DOI: 10.3389/fendo.2023.1124408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/07/2023] [Indexed: 02/18/2023] Open
Abstract
Brown and beige adipose tissues regulate body energy expenditure through adaptive thermogenesis, which converts energy into heat by oxidative phosphorylation uncoupling. Although promoting adaptive thermogenesis has been demonstrated to be a prospective strategy for obesity control, there are few methods for increasing adipose tissue thermogenesis in a safe and effective way. Histone deacetylase (HDAC) is a category of epigenetic modifying enzymes that catalyzes deacetylation on both histone and non-histone proteins. Recent studies illustrated that HDACs play an important role in adipose tissue thermogenesis through modulating gene transcription and chromatin structure as well as cellular signals transduction in both deacetylation dependent or independent manners. Given that different classes and subtypes of HDACs show diversity in the mechanisms of adaptive thermogenesis regulation, we systematically summarized the effects of different HDACs on adaptive thermogenesis and their underlying mechanisms in this review. We also emphasized the differences among HDACs in thermogenesis regulation, which will help to find new efficient anti-obesity drugs targeting specific HDAC subtypes.
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Affiliation(s)
- Ruonan Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Cao
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yingying Xiang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Penghua Fang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenbin Shang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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18
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Scheidl TB, Brightwell AL, Easson SH, Thompson JA. Maternal obesity and programming of metabolic syndrome in the offspring: searching for mechanisms in the adipocyte progenitor pool. BMC Med 2023; 21:50. [PMID: 36782211 PMCID: PMC9924890 DOI: 10.1186/s12916-023-02730-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 01/09/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND It is now understood that it is the quality rather than the absolute amount of adipose tissue that confers risk for obesity-associated disease. Adipose-derived stem cells give rise to adipocytes during the developmental establishment of adipose depots. In adult depots, a reservoir of progenitors serves to replace adipocytes that have reached their lifespan and for recruitment to increase lipid buffering capacity under conditions of positive energy balance. MAIN: The adipose tissue expandability hypothesis posits that a failure in de novo differentiation of adipocytes limits lipid storage capacity and leads to spillover of lipids into the circulation, precipitating the onset of obesity-associated disease. Since adipose progenitors are specified to their fate during late fetal life, perturbations in the intrauterine environment may influence the rapid expansion of adipose depots that occurs in childhood or progenitor function in established adult depots. Neonates born to mothers with obesity or diabetes during pregnancy tend to have excessive adiposity at birth and are at increased risk for childhood adiposity and cardiometabolic disease. CONCLUSION In this narrative review, we synthesize current knowledge in the fields of obesity and developmental biology together with literature from the field of the developmental origins of health and disease (DOHaD) to put forth the hypothesis that the intrauterine milieu of pregnancies complicated by maternal metabolic disease disturbs adipogenesis in the fetus, thereby accelerating the trajectory of adipose expansion in early postnatal life and predisposing to impaired adipose plasticity.
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Affiliation(s)
- Taylor B. Scheidl
- Cumming School of Medicine, Calgary, Canada
- Alberta Children’s Hospital Research Institute, Calgary, Canada
- Libin Cardiovascular Institute, Calgary, Canada
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
| | - Amy L. Brightwell
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
| | - Sarah H. Easson
- Cumming School of Medicine, Calgary, Canada
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
| | - Jennifer A. Thompson
- Cumming School of Medicine, Calgary, Canada
- Alberta Children’s Hospital Research Institute, Calgary, Canada
- Libin Cardiovascular Institute, Calgary, Canada
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
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Machado SA, Pasquarelli-do-Nascimento G, da Silva DS, Farias GR, de Oliveira Santos I, Baptista LB, Magalhães KG. Browning of the white adipose tissue regulation: new insights into nutritional and metabolic relevance in health and diseases. Nutr Metab (Lond) 2022; 19:61. [PMID: 36068578 PMCID: PMC9446768 DOI: 10.1186/s12986-022-00694-0] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/19/2022] [Indexed: 12/11/2022] Open
Abstract
Adipose tissues are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. Although white adipose tissue and brown adipose tissue are currently considered key endocrine organs, they differ functionally and morphologically. The existence of the beige or brite adipocytes, cells displaying intermediary characteristics between white and brown adipocytes, illustrates the plastic nature of the adipose tissue. These cells are generated through white adipose tissue browning, a process associated with augmented non-shivering thermogenesis and metabolic capacity. This process involves the upregulation of the uncoupling protein 1, a molecule that uncouples the respiratory chain from Adenosine triphosphate synthesis, producing heat. β-3 adrenergic receptor system is one important mediator of white adipose tissue browning, during cold exposure. Surprisingly, hyperthermia may also induce beige activation and white adipose tissue beiging. Physical exercising copes with increased levels of specific molecules, including Beta-Aminoisobutyric acid, irisin, and Fibroblast growth factor 21 (FGF21), which induce adipose tissue browning. FGF21 is a stress-responsive hormone that interacts with beta-klotho. The central roles played by hormones in the browning process highlight the relevance of the individual lifestyle, including circadian rhythm and diet. Circadian rhythm involves the sleep-wake cycle and is regulated by melatonin, a hormone associated with UCP1 level upregulation. In contrast to the pro-inflammatory and adipose tissue disrupting effects of the western diet, specific food items, including capsaicin and n-3 polyunsaturated fatty acids, and dietary interventions such as calorie restriction and intermittent fasting, favor white adipose tissue browning and metabolic efficiency. The intestinal microbiome has also been pictured as a key factor in regulating white tissue browning, as it modulates bile acid levels, important molecules for the thermogenic program activation. During embryogenesis, in which adipose tissue formation is affected by Bone morphogenetic proteins that regulate gene expression, the stimuli herein discussed influence an orchestra of gene expression regulators, including a plethora of transcription factors, and chromatin remodeling enzymes, and non-coding RNAs. Considering the detrimental effects of adipose tissue browning and the disparities between adipose tissue characteristics in mice and humans, further efforts will benefit a better understanding of adipose tissue plasticity biology and its applicability to managing the overwhelming burden of several chronic diseases.
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Affiliation(s)
- Sabrina Azevedo Machado
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil
| | | | - Debora Santos da Silva
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil
| | - Gabriel Ribeiro Farias
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil
| | - Igor de Oliveira Santos
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil
| | - Luana Borges Baptista
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil
| | - Kelly Grace Magalhães
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil.
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20
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Goo B, Ahmadieh S, Zarzour A, Yiew NKH, Kim D, Shi H, Greenway J, Cave S, Nguyen J, Aribindi S, Wendolowski M, Veerapaneni P, Ogbi M, Chen W, Lei Y, Lu XY, Kim HW, Weintraub NL. Sex-Dependent Role of Adipose Tissue HDAC9 in Diet-Induced Obesity and Metabolic Dysfunction. Cells 2022; 11:2698. [PMID: 36078104 PMCID: PMC9454798 DOI: 10.3390/cells11172698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is a major risk factor for both metabolic and cardiovascular disease. We reported that, in obese male mice, histone deacetylase 9 (HDAC9) is upregulated in adipose tissues, and global deletion of HDAC9 protected against high fat diet (HFD)-induced obesity and metabolic disease. Here, we investigated the impact of adipocyte-specific HDAC9 gene deletion on diet-induced obesity in male and female mice. The HDAC9 gene expression was increased in adipose tissues of obese male and female mice and HDAC9 expression correlated positively with body mass index in humans. Interestingly, female, but not male, adipocyte-specific HDAC9 KO mice on HFD exhibited reduced body weight and visceral adipose tissue mass, adipocyte hypertrophy, and improved insulin sensitivity, glucose tolerance and adipogenic differentiation gene expression. Furthermore, adipocyte-specific HDAC9 gene deletion in female mice improved metabolic health as assessed by whole body energy expenditure, oxygen consumption, and adaptive thermogenesis. Mechanistically, compared to female mice, HFD-fed male mice exhibited preferential HDAC9 expression in the stromovascular fraction, which may have offset the impact of adipocyte-specific HDAC9 gene deletion in male mice. These results suggest that HDAC9 expressed in adipocytes is detrimental to obesity in female mice and provides novel evidence of sex-related differences in HDAC9 cellular expression and contribution to obesity-related metabolic disease.
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Affiliation(s)
- Brandee Goo
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Samah Ahmadieh
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
- Department of Medicine, Medical College of Georgia, Augusta University, 1120 15th St., BI5076, Augusta, GA 30912, USA
| | - Abdalrahman Zarzour
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
- Department of Medicine, Medical College of Georgia, Augusta University, 1120 15th St., BI5076, Augusta, GA 30912, USA
| | - Nicole K. H. Yiew
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - David Kim
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Hong Shi
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
- Department of Medicine, Medical College of Georgia, Augusta University, 1120 15th St., BI5076, Augusta, GA 30912, USA
| | - Jacob Greenway
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Stephen Cave
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Jenny Nguyen
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Swetha Aribindi
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Mark Wendolowski
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Praneet Veerapaneni
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Mourad Ogbi
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
| | - Weiqin Chen
- Departments of Physiology and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th St., CA3126, Augusta, GA 30912, USA
| | - Yun Lei
- Departments of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th St., CA3008, Augusta, GA 30912, USA
| | - Xin-Yun Lu
- Departments of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th St., CA3008, Augusta, GA 30912, USA
| | - Ha Won Kim
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
- Department of Medicine, Medical College of Georgia, Augusta University, 1120 15th St., BI5076, Augusta, GA 30912, USA
| | - Neal L. Weintraub
- Vascular Biology Center, Medical College of Georgia, Augusta University, 1120 15th St., CB3940, Augusta, GA 30912, USA
- Department of Medicine, Medical College of Georgia, Augusta University, 1120 15th St., BI5076, Augusta, GA 30912, USA
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21
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Lu Y, Zhang Y, Zhao X, Shang C, Xiang M, Li L, Cui X. Microbiota-derived short-chain fatty acids: Implications for cardiovascular and metabolic disease. Front Cardiovasc Med 2022; 9:900381. [PMID: 36035928 PMCID: PMC9403138 DOI: 10.3389/fcvm.2022.900381] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular diseases (CVDs) have been on the rise around the globe in the past few decades despite the existing guidelines for prevention and treatment. Short-chain fatty acids (SCFAs) are the main metabolites of certain colonic anaerobic bacterial fermentation in the gastrointestinal tract and have been found to be the key metabolites in the host of CVDs. Accumulating evidence suggest that the end-products of SCFAs (including acetate, propionate, and butyrate) interact with CVDs through maintaining intestinal integrity, anti-inflammation, modulating glucolipid metabolism, blood pressure, and activating gut-brain axis. Recent advances suggest a promising way to prevent and treat CVDs by controlling SCFAs. Hence, this review tends to summarize the functional roles carried out by SCFAs that are reported in CVDs studies. This review also highlights several novel therapeutic interventions for SCFAs to prevent and treat CVDs.
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Affiliation(s)
- Yingdong Lu
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yang Zhang
- First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xin Zhao
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chang Shang
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mi Xiang
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Li Li,
| | - Xiangning Cui
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Xiangning Cui,
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22
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Zinc-dependent histone deacetylases: Potential therapeutic targets for arterial hypertension. Biochem Pharmacol 2022; 202:115111. [DOI: 10.1016/j.bcp.2022.115111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 11/23/2022]
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23
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Li Y, Li J, Yu H, Liu Y, Song H, Tian X, Liu D, Yan C, Han Y. HOXA5-miR-574-5p axis promotes adipogenesis and alleviates insulin resistance. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:200-210. [PMID: 34976438 PMCID: PMC8693313 DOI: 10.1016/j.omtn.2021.08.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 08/31/2021] [Indexed: 11/15/2022]
Abstract
Differentiation of preadipocytes into functional adipocytes could be a major target for repressing obesity-induced insulin resistance (IR). However, the molecular mechanisms involved in adipogenesis and the development of IR are unclear. We report, for the first time, that miR-574-5p, a novel miRNA, promotes adipogenesis to suppress IR. An increase in the level of miR-574-5p significantly induced the differentiation of preadipocytes into mature adipocytes. Conversely, reduction of miR-574-5p levels blocked the differentiation of preadipocytes in vitro. In a dual-luciferase reporter assay, it was shown that homeobox A5 (HOXA5) promoted the transcription of miR-574-5p to induce the differentiation of preadipocytes. Hdac9, a direct downstream target of miR-574-5p, was involved in the regulation of adipocyte differentiation. The overexpression of miR-574-5p also promoted adipogenesis in subcutaneous fat to alleviate IR in high-fat-diet-fed mice. Additionally, miR-574-5p expression was significantly higher in the subcutaneous adipose tissue of obese patients without type 2 diabetes than in those with type 2 diabetes. There was an increase in HOXA5 expression and a decrease in histone deacetylase 9 (HDAC9) expression in the subcutaneous fat of obese patients without type 2 diabetes. These results suggest that miR-574-5p may be a potential therapeutic target for combating obesity-related IR.
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Affiliation(s)
- Yuying Li
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jiayin Li
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang 110016, China
| | - Haibo Yu
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
| | - Yanxia Liu
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
| | - Haixu Song
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
| | - Xiaoxiang Tian
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
| | - Dan Liu
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
| | - Chenghui Yan
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
| | - Yaling Han
- Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang 110016, China
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24
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Zarkasi KA, Abdul Murad NA, Ahmad N, Jamal R, Abdullah N. Coronary Heart Disease in Type 2 Diabetes Mellitus: Genetic Factors and Their Mechanisms, Gene-Gene, and Gene-Environment Interactions in the Asian Populations. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:647. [PMID: 35055468 PMCID: PMC8775550 DOI: 10.3390/ijerph19020647] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 02/04/2023]
Abstract
Asians are more susceptible to type 2 diabetes mellitus (T2D) and its coronary heart disease (CHD) complications than the Western populations, possibly due to genetic factors, higher degrees of obesity, insulin resistance, and endothelial dysfunction that could occur even in healthy individuals. The genetic factors and their mechanisms, along with gene-gene and gene-environment interactions associated with CHD in T2D Asians, are yet to be explored. Therefore, the objectives of this paper were to review the current evidence of genetic factors for CHD, summarize the proposed mechanisms of these genes and how they may associate with CHD risk, and review the gene-gene and gene-environment interactions in T2D Asians with CHD. The genetic factors can be grouped according to their involvement in the energy and lipoprotein metabolism, vascular and endothelial pathology, antioxidation, cell cycle regulation, DNA damage repair, hormonal regulation of glucose metabolism, as well as cytoskeletal function and intracellular transport. Meanwhile, interactions between single nucleotide polymorphisms (SNPs) from different genes, SNPs within a single gene, and genetic interaction with environmental factors including obesity, smoking habit, and hyperlipidemia could modify the gene's effect on the disease risk. Collectively, these factors illustrate the complexities of CHD in T2D, specifically among Asians.
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Affiliation(s)
- Khairul Anwar Zarkasi
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia; (K.A.Z.); (N.A.A.M.); (R.J.)
- Biochemistry Unit, Preclinical Department, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia, Kuala Lumpur 57000, Malaysia
| | - Nor Azian Abdul Murad
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia; (K.A.Z.); (N.A.A.M.); (R.J.)
| | - Norfazilah Ahmad
- Epidemiology and Statistics Unit, Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia;
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia; (K.A.Z.); (N.A.A.M.); (R.J.)
| | - Noraidatulakma Abdullah
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia; (K.A.Z.); (N.A.A.M.); (R.J.)
- Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
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25
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Mikolajczak A, Sallam NA, Singh RD, Scheidl TB, Walsh EJ, Larion S, Huang C, Thompson JA. Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction. Am J Physiol Endocrinol Metab 2021; 321:E581-E591. [PMID: 34459218 PMCID: PMC8791794 DOI: 10.1152/ajpendo.00229.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.
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Affiliation(s)
- Anna Mikolajczak
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
| | - Nada A Sallam
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Faculty of Pharmacy, Cairo University, Giza, Egypt
| | - Radha D Singh
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | - Taylor B Scheidl
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
| | - Emma J Walsh
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sebastian Larion
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina
| | - Carol Huang
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
| | - Jennifer A Thompson
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
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26
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Gao W, Liu JL, Lu X, Yang Q. Epigenetic regulation of energy metabolism in obesity. J Mol Cell Biol 2021; 13:480-499. [PMID: 34289049 PMCID: PMC8530523 DOI: 10.1093/jmcb/mjab043] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/24/2021] [Accepted: 05/12/2021] [Indexed: 11/13/2022] Open
Abstract
Obesity has reached epidemic proportions globally. Although modern adoption of a sedentary lifestyle coupled with energy-dense nutrition is considered to be the main cause of obesity epidemic, genetic preposition contributes significantly to the imbalanced energy metabolism in obesity. However, the variants of genetic loci identified from large-scale genetic studies do not appear to fully explain the rapid increase in obesity epidemic in the last four to five decades. Recent advancements of next-generation sequencing technologies and studies of tissue-specific effects of epigenetic factors in metabolic organs have significantly advanced our understanding of epigenetic regulation of energy metabolism in obesity. The epigenome, including DNA methylation, histone modifications, and RNA-mediated processes, is characterized as mitotically or meiotically heritable changes in gene function without alteration of DNA sequence. Importantly, epigenetic modifications are reversible. Therefore, comprehensively understanding the landscape of epigenetic regulation of energy metabolism could unravel novel molecular targets for obesity treatment. In this review, we summarize the current knowledge on the roles of DNA methylation, histone modifications such as methylation and acetylation, and RNA-mediated processes in regulating energy metabolism. We also discuss the effects of lifestyle modifications and therapeutic agents on epigenetic regulation of energy metabolism in obesity.
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Affiliation(s)
- Wei Gao
- Department of Geriatrics, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 211166, China
| | - Jia-Li Liu
- Department of Geriatrics, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 211166, China
| | - Xiang Lu
- Department of Geriatrics, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 211166, China
| | - Qin Yang
- Department of Medicine, Physiology and Biophysics, UC Irvine Diabetes Center, University of California Irvine, Irvine, CA 92697, USA
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27
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Yang C, Croteau S, Hardy P. Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer. Cell Oncol (Dordr) 2021; 44:997-1017. [PMID: 34318404 PMCID: PMC8516780 DOI: 10.1007/s13402-021-00626-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. CONCLUSIONS This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.
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Affiliation(s)
- Chun Yang
- Research Center of CHU Sainte-Justine, University of Montréal, 3175 Côte-Sainte-Catherine, Room 2.17.004, Montréal, Québec H3T 1C5 Canada
| | - Stéphane Croteau
- Departments of Medicine, Pediatrics, Pharmacology and Physiology, University of Montréal, Montréal, QC Canada
| | - Pierre Hardy
- Research Center of CHU Sainte-Justine, University of Montréal, 3175 Côte-Sainte-Catherine, Room 2.17.004, Montréal, Québec H3T 1C5 Canada
- Departments of Medicine, Pediatrics, Pharmacology and Physiology, University of Montréal, Montréal, QC Canada
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Pyruvate dehydrogenase kinase 1 and 2 deficiency reduces high-fat diet-induced hypertrophic obesity and inhibits the differentiation of preadipocytes into mature adipocytes. Exp Mol Med 2021; 53:1390-1401. [PMID: 34552205 PMCID: PMC8492875 DOI: 10.1038/s12276-021-00672-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 06/07/2021] [Accepted: 06/24/2021] [Indexed: 12/02/2022] Open
Abstract
Obesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity. The discovery that two forms of a key enzyme appear to play a critical role in fat production triggered by overeating might lead to new approaches to prevent and treat obesity. Hyeon-Ji Kang at Kyungpook National University, Daegu, South Korea, and colleagues in South Korea and the USA examined the role of the enzymes pyruvate dehydrogenase kinase types 1 and 2 (PDK1/2). PDK enzymes regulate the activity of a multi-enzyme complex that catalyzes a key step in the use of glucose to provide energy stores for cells. Mice deficient in PDK2 were protected from diet-induced obesity, and PDK 1 and 2 activity was increased during the generation of fat cells. Studies using mice and human fat tissue confirmed that the enzymes regulate the development and growth of fat cells. Drugs inhibiting PDK enzymes might combat obesity.
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Liu Y, Du M, Lin HY. Histone deacetylase 9 deficiency exaggerates uterine M2 macrophage polarization. J Cell Mol Med 2021; 25:7690-7708. [PMID: 34145738 PMCID: PMC8358884 DOI: 10.1111/jcmm.16616] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/23/2021] [Accepted: 04/29/2021] [Indexed: 12/16/2022] Open
Abstract
The maternal‐foetal interface is an immune‐privileged site where the semi‐allogeneic embryo is protected from attacks by the maternal immune system. Uterine macrophages are key players in establishing and maintaining pregnancy, and the dysregulation of the M1‐M2 subpopulation balance causes abortion. We separated two distinct mouse uterine macrophage subpopulations during early pregnancy, CD45+F4/80+CD206− M1‐like (M1) and CD45+F4/80+CD206+ M2‐like (M2) cells. The M1 preponderance was significantly exaggerated at 6 hours after lipopolysaccharide (LPS) treatment, and adoptive transfer of M2 macrophages partially rescued LPS‐induced abortion. RNA sequencing analysis of mouse uterine M2 versus M1 revealed 1837 differentially expressed genes (DEGs), among which 629 was up‐regulated and 1208 was down‐regulated. Histone deacetylase 9 (Hdac9) was one of the DEGs and validated to be significantly up‐regulated in uterine M2 as compared with M1. Remarkably, this differential expression profile between M1 and M2 was also evident in primary splenic macrophages and in vitro polarized murine peritoneal, bone marrow–derived and RAW 264.7 macrophages. In Hdac9/HDAC9 knockout RAW 264.7 and human THP‐1–derived macrophages, the expression of M1 differentiation markers was unchanged or decreased whereas M2 markers were increased compared with the wild‐type cells, and these effects were unrelated to compromised proliferation. Furthermore, Hdac9/HDAC9 ablation significantly enhanced the phagocytosis of fluorescent microspheres in M2 Raw 264.7 cells yet decreased the capacity of THP‐1‐derived M1 macrophages. The above results demonstrate that Hdac9/HDAC9 deficiency exaggerates M2 macrophage polarization in mouse and human macrophages, which may provide clues for our understanding of the epigenetic regulation on macrophage M1/M2 polarization in maternal‐foetal tolerance.
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Affiliation(s)
- Yanqin Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute of Physical Science and Information Technology, Anhui University, Hefei, China.,State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China
| | - Meirong Du
- Gynecology and Obstetrics Hospital, Fudan University, Shanghai, China
| | - Hai-Yan Lin
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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30
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Dewanjee S, Vallamkondu J, Kalra RS, Chakraborty P, Gangopadhyay M, Sahu R, Medala V, John A, Reddy PH, De Feo V, Kandimalla R. The Emerging Role of HDACs: Pathology and Therapeutic Targets in Diabetes Mellitus. Cells 2021; 10:1340. [PMID: 34071497 PMCID: PMC8228721 DOI: 10.3390/cells10061340] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/22/2021] [Accepted: 05/26/2021] [Indexed: 12/22/2022] Open
Abstract
Diabetes mellitus (DM) is one of the principal manifestations of metabolic syndrome and its prevalence with modern lifestyle is increasing incessantly. Chronic hyperglycemia can induce several vascular complications that were referred to be the major cause of morbidity and mortality in DM. Although several therapeutic targets have been identified and accessed clinically, the imminent risk of DM and its prevalence are still ascending. Substantial pieces of evidence revealed that histone deacetylase (HDAC) isoforms can regulate various molecular activities in DM via epigenetic and post-translational regulation of several transcription factors. To date, 18 HDAC isoforms have been identified in mammals that were categorized into four different classes. Classes I, II, and IV are regarded as classical HDACs, which operate through a Zn-based mechanism. In contrast, class III HDACs or Sirtuins depend on nicotinamide adenine dinucleotide (NAD+) for their molecular activity. Functionally, most of the HDAC isoforms can regulate β cell fate, insulin release, insulin expression and signaling, and glucose metabolism. Moreover, the roles of HDAC members have been implicated in the regulation of oxidative stress, inflammation, apoptosis, fibrosis, and other pathological events, which substantially contribute to diabetes-related vascular dysfunctions. Therefore, HDACs could serve as the potential therapeutic target in DM towards developing novel intervention strategies. This review sheds light on the emerging role of HDACs/isoforms in diabetic pathophysiology and emphasized the scope of their targeting in DM for constituting novel interventional strategies for metabolic disorders/complications.
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Affiliation(s)
- Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, West Bengal, India;
| | | | - Rajkumar Singh Kalra
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Higashi 1-1-1, Tsukuba 305 8565, Japan;
| | - Pratik Chakraborty
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, West Bengal, India;
| | - Moumita Gangopadhyay
- School of Life Science and Biotechnology, ADAMAS University, Barasat, Kolkata 700126, West Bengal, India;
| | - Ranabir Sahu
- Department of Pharmaceutical Technology, University of North Bengal, Darjeeling 734013, West Bengal, India;
| | - Vijaykrishna Medala
- Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India;
| | - Albin John
- Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.J.); (P.H.R.)
| | - P. Hemachandra Reddy
- Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (A.J.); (P.H.R.)
- Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Vincenzo De Feo
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy
| | - Ramesh Kandimalla
- Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India;
- Department of Biochemistry, Kakatiya Medical College, Warangal 506007, Telangana, India
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31
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Chu XY, Zhang CC, Zhang RX, Zhang JF, Xia B, Wu JW. Identification of Dacinostat as a potential anti-obesity compound through transcriptional activation of adipose thermogenesis in mice. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166169. [PMID: 34000373 DOI: 10.1016/j.bbadis.2021.166169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 10/21/2022]
Abstract
Obesity is a worldwide health problem. Activating fat mobilization and reducing fat synthesis is a promising strategy to mitigate obesity and its complicated metabolic diseases. However, few clinically effective and safe agents conform to the strategy. In the present study, by screening the next-generation L1000-based CMAP small molecule library, we identify histone deacetylase inhibitor Dacinostat, which has been previously tested in clinical trials for patients with advanced solid tumors, as an anti-obesity candidate. Administration of Dacinostat prevents high-fat diet-induced obesity, insulin resistance, and fatty liver in mice without causing adverse effects. Dacinostat treatment enhances adipose thermogenesis as shown by elevated body temperature, accompanied with high mRNA expression of Ucp1 and Ppargc1α. Mechanistically, we show that the thermogenic effect of Dacinostat is achieved by acetylation of histone 3 lysine 27 mediated transcriptional activation of Ucp1 and Ppargc1α in adipose tissue. In conclusion, these findings suggest that Dacinostat is a potential anti-obesity compound through transcriptional activation of adipose thermogenesis.
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Affiliation(s)
- Xin Yi Chu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Cong Cong Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Rui Xin Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jian Feng Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Bo Xia
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jiang Wei Wu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
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32
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Callaghan MA, Alatorre-Hinojosa S, Connors LT, Singh RD, Thompson JA. Plasticizers and Cardiovascular Health: Role of Adipose Tissue Dysfunction. Front Pharmacol 2021; 11:626448. [PMID: 33716730 PMCID: PMC7947604 DOI: 10.3389/fphar.2020.626448] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022] Open
Abstract
Since the 1950s, the production of plastics has increased 200-fold, reaching 360 million tonnes in 2019. Plasticizers, additives that modify the flexibility and rigidity of the product, are ingested as they migrate into food and beverages. Human exposure is continuous and widespread; between 75 and 97% of urine samples contain detectable levels of bisphenols and phthalates, the most common plasticizers. Concern over the toxicity of plasticizers arose in the late 1990s, largely focused around adverse developmental and reproductive effects. More recently, many studies have demonstrated that exposure to plasticizers increases the risk for obesity, type 2 diabetes, and cardiovascular disease (CVD). In the 2000s, many governments including Canada, the United States and European countries restricted the use of certain plasticizers in products targeted towards infants and children. Resultant consumer pressure motivated manufacturers to substitute plasticizers with analogues, which have been marketed as safe. However, data on the effects of these new substitutes are limited and data available to-date suggest that many exhibit similar properties to the chemicals they replaced. The adverse effects of plasticizers have largely been attributed to their endocrine disrupting properties, which modulate hormone signaling. Adipose tissue has been well-documented to be a target of the disrupting effects of both bisphenols and phthalates. Since adipose tissue function is a key determinant of cardiovascular health, adverse effects of plasticizers on adipocyte signaling and function may underlie their link to cardiovascular disease. Herein, we discuss the current evidence linking bisphenols and phthalates to obesity and CVD and consider how documented impacts of these plasticizers on adipocyte function may contribute to the development of CVD.
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Affiliation(s)
- Mikyla A Callaghan
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | | | - Liam T Connors
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Radha D Singh
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Jennifer A Thompson
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada.,Alberta Children's Health Research Institute, Calgary, AB, Canada
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33
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Tritz R, Benson T, Harris V, Hudson FZ, Mintz J, Zhang H, Kennard S, Chen W, Stepp DW, Csanyi G, Belin de Chantemèle EJ, Weintraub NL, Stansfield BK. Nf1 heterozygous mice recapitulate the anthropometric and metabolic features of human neurofibromatosis type 1. Transl Res 2021; 228:52-63. [PMID: 32781282 PMCID: PMC7779711 DOI: 10.1016/j.trsl.2020.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/29/2020] [Accepted: 08/04/2020] [Indexed: 12/26/2022]
Abstract
Neurofibromatosis type 1 (NF1) is a heritable cancer predisposition syndrome resulting from mutations in the NF1 tumor suppressor gene. Genotype-phenotype correlations for NF1 are rare due to the large number of NF1 mutations and role of modifier genes in manifestations of NF1; however, emerging reports suggest that persons with NF1 display a distinct anthropometric and metabolic phenotype featuring short stature, low body mass index, increased insulin sensitivity, and protection from diabetes. Nf1 heterozygous (Nf1+/-) mice accurately reflect the dominant inheritance of NF1 and are regularly employed as a model of NF1. Here, we sought to identify whether Nf1+/- mice recapitulate the anthropometric and metabolic features identified in persons with NF1. Littermate 16-20 week-old male wildtype (WT) and Nf1+/- C57B/6J mice underwent nuclear magnetic resonance (NMR), indirect calorimetry, and glucose/insulin/pyruvate tolerance testing. In some experiments, tissues were harvested for NMR and histologic characterization. Nf1+/- mice are leaner with significantly reduced visceral and subcutaneous fat mass, which corresponds with an increased density of small adipocytes and reduced leptin levels. Additionally, Nf1+/- mice are highly reliant on carbohydrates as an energy substrate and display increased glucose clearance and insulin sensitivity, but normal response to pyruvate suggesting enhanced glucose utilization and preserved gluconeogenesis. Finally, WT and Nf1+/- mice subjected to high glucose diet were protected from diet-induced obesity and hyperglycemia. Our data suggest that Nf1+/- mice closely recapitulate the anthropometric and metabolic phenotype identified in persons with NF1, which will impact the interpretation of previous and future translational studies of NF1.
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Affiliation(s)
- Rebekah Tritz
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Tyler Benson
- Vascular Biology Center, Augusta University, Augusta, Georgia
| | - Valerie Harris
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Farlyn Z Hudson
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - James Mintz
- Vascular Biology Center, Augusta University, Augusta, Georgia
| | - Hanfang Zhang
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Simone Kennard
- Vascular Biology Center, Augusta University, Augusta, Georgia
| | - Weiqin Chen
- Vascular Biology Center, Augusta University, Augusta, Georgia
| | - David W Stepp
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Gabor Csanyi
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Eric J Belin de Chantemèle
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Neal L Weintraub
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Brian K Stansfield
- Vascular Biology Center, Augusta University, Augusta, Georgia; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia.
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34
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Brancolini C, Di Giorgio E, Formisano L, Gagliano T. Quis Custodiet Ipsos Custodes (Who Controls the Controllers)? Two Decades of Studies on HDAC9. Life (Basel) 2021; 11:life11020090. [PMID: 33513699 PMCID: PMC7912504 DOI: 10.3390/life11020090] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 01/20/2021] [Accepted: 01/24/2021] [Indexed: 12/21/2022] Open
Abstract
Understanding how an epigenetic regulator drives different cellular responses can be a tricky task. Very often, their activities are modulated by large multiprotein complexes, the composition of which is context- and time-dependent. As a consequence, experiments aimed to unveil the functions of an epigenetic regulator can provide different outcomes and conclusions, depending on the circumstances. HDAC9 (histone deacetylase), an epigenetic regulator that influences different differentiating and adaptive responses, makes no exception. Since its discovery, different phenotypes and/or dysfunctions have been observed after the artificial manipulation of its expression. The cells and the microenvironment use multiple strategies to control and monitor HDAC9 activities. To date, some of the genes under HDAC9 control have been identified. However, the exact mechanisms through which HDAC9 can achieve all the different tasks so far described, remain mysterious. Whether it can assemble into different multiprotein complexes and how the cells modulate these complexes is not clearly defined. In summary, despite several cellular responses are known to be affected by HDAC9, many aspects of its network of interactions still remain to be defined.
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Affiliation(s)
- Claudio Brancolini
- Department of Medicine, Università degli Studi di Udine, p.le Kolbe 4, 33100 Udine, Italy; (E.D.G.); (T.G.)
- Correspondence:
| | - Eros Di Giorgio
- Department of Medicine, Università degli Studi di Udine, p.le Kolbe 4, 33100 Udine, Italy; (E.D.G.); (T.G.)
| | - Luigi Formisano
- Department of Neuroscience, School of Medicine, “Federico II” University of Naples, Via Pansini, 5, 80131 Naples, Italy;
| | - Teresa Gagliano
- Department of Medicine, Università degli Studi di Udine, p.le Kolbe 4, 33100 Udine, Italy; (E.D.G.); (T.G.)
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Pant R, Firmal P, Shah VK, Alam A, Chattopadhyay S. Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome. Front Cell Dev Biol 2021; 8:619888. [PMID: 33511131 PMCID: PMC7835429 DOI: 10.3389/fcell.2020.619888] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is one of the biggest public health concerns identified by an increase in adipose tissue mass as a result of adipocyte hypertrophy and hyperplasia. Pertaining to the importance of adipose tissue in various biological processes, any alteration in its function results in impaired metabolic health. In this review, we discuss how adipose tissue maintains the metabolic health through secretion of various adipokines and inflammatory mediators and how its dysfunction leads to the development of severe metabolic disorders and influences cancer progression. Impairment in the adipocyte function occurs due to individuals' genetics and/or environmental factor(s) that largely affect the epigenetic profile leading to altered gene expression and onset of obesity in adults. Moreover, several crucial aspects of adipose biology, including the regulation of different transcription factors, are controlled by epigenetic events. Therefore, understanding the intricacies of adipogenesis is crucial for recognizing its relevance in underlying disease conditions and identifying the therapeutic interventions for obesity and metabolic syndrome.
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Affiliation(s)
- Richa Pant
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Priyanka Firmal
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Vibhuti Kumar Shah
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Aftab Alam
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Samit Chattopadhyay
- National Centre for Cell Science, SP Pune University Campus, Pune, India.,Department of Biological Sciences, BITS Pilani, Goa, India
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36
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Nanduri R. Epigenetic Regulators of White Adipocyte Browning. EPIGENOMES 2021; 5:3. [PMID: 34968255 PMCID: PMC8594687 DOI: 10.3390/epigenomes5010003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/16/2020] [Accepted: 01/06/2021] [Indexed: 12/15/2022] Open
Abstract
Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.
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Affiliation(s)
- Ravikanth Nanduri
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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37
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Joshi H, Vastrad B, Joshi N, Vastrad C, Tengli A, Kotturshetti I. Identification of Key Pathways and Genes in Obesity Using Bioinformatics Analysis and Molecular Docking Studies. Front Endocrinol (Lausanne) 2021; 12:628907. [PMID: 34248836 PMCID: PMC8264660 DOI: 10.3389/fendo.2021.628907] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 05/19/2021] [Indexed: 01/01/2023] Open
Abstract
Obesity is an excess accumulation of body fat. Its progression rate has remained high in recent years. Therefore, the aim of this study was to diagnose important differentially expressed genes (DEGs) associated in its development, which may be used as novel biomarkers or potential therapeutic targets for obesity. The gene expression profile of E-MTAB-6728 was downloaded from the database. After screening DEGs in each ArrayExpress dataset, we further used the robust rank aggregation method to diagnose 876 significant DEGs including 438 up regulated and 438 down regulated genes. Functional enrichment analysis was performed. These DEGs were shown to be significantly enriched in different obesity related pathways and GO functions. Then protein-protein interaction network, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. The module analysis was performed based on the whole PPI network. We finally filtered out STAT3, CORO1C, SERPINH1, MVP, ITGB5, PCM1, SIRT1, EEF1G, PTEN and RPS2 hub genes. Hub genes were validated by ICH analysis, receiver operating curve (ROC) analysis and RT-PCR. Finally a molecular docking study was performed to find small drug molecules. The robust DEGs linked with the development of obesity were screened through the expression profile, and integrated bioinformatics analysis was conducted. Our study provides reliable molecular biomarkers for screening and diagnosis, prognosis as well as novel therapeutic targets for obesity.
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Affiliation(s)
- Harish Joshi
- Department of Endocrinology, Endocrine and Diabetes Care Center, Hubbali, India
| | - Basavaraj Vastrad
- Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, India
| | - Nidhi Joshi
- Department of Medicine, Dr. D. Y. Patil Medical College, Kolhapur, India
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad, India
- *Correspondence: Chanabasayya Vastrad,
| | - Anandkumar Tengli
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru and JSS Academy of Higher Education & Research, Mysuru, India
| | - Iranna Kotturshetti
- Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, India
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38
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Asif S, Morrow NM, Mulvihill EE, Kim KH. Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases. Front Genet 2020; 11:590369. [PMID: 33193730 PMCID: PMC7593700 DOI: 10.3389/fgene.2020.590369] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022] Open
Abstract
The global prevalence of metabolic disorders, such as obesity, diabetes and fatty liver disease, is dramatically increasing. Both genetic and environmental factors are well-known contributors to the development of these diseases and therefore, the study of epigenetics can provide additional mechanistic insight. Dietary interventions, including caloric restriction, intermittent fasting or time-restricted feeding, have shown promising improvements in patients' overall metabolic profiles (i.e., reduced body weight, improved glucose homeostasis), and an increasing number of studies have associated these beneficial effects with epigenetic alterations. In this article, we review epigenetic changes involved in both metabolic diseases and dietary interventions in primary metabolic tissues (i.e., adipose, liver, and pancreas) in hopes of elucidating potential biomarkers and therapeutic targets for disease prevention and treatment.
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Affiliation(s)
- Shaza Asif
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Nadya M. Morrow
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Erin E. Mulvihill
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Kyoung-Han Kim
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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39
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Wang W, Liu Z, Zhang X, Liu J, Gui J, Cui M, Li Y. miR‐211‐5p is down‐regulated and a prognostic marker in bladder cancer. J Gene Med 2020; 22:e3270. [PMID: 32893379 DOI: 10.1002/jgm.3270] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 08/17/2020] [Accepted: 08/30/2020] [Indexed: 12/27/2022] Open
Affiliation(s)
- Weisheng Wang
- Department of Urinary Surgery The Qujing No. 1 People's Hospital Qujing Yunnan Province China
| | - Zhiming Liu
- Department of Urinary Surgery The Qujing No. 1 People's Hospital Qujing Yunnan Province China
| | - Xuegang Zhang
- Department of Urinary Surgery The Qujing No. 1 People's Hospital Qujing Yunnan Province China
| | - Junning Liu
- Department of Urinary Surgery The Qujing No. 1 People's Hospital Qujing Yunnan Province China
| | - Junqing Gui
- Department of Urinary Surgery The Qujing No. 1 People's Hospital Qujing Yunnan Province China
| | - Maorong Cui
- Department of Urinary Surgery The Qujing No. 1 People's Hospital Qujing Yunnan Province China
| | - Yong Li
- Department of Urinary Surgery The Qujing No. 1 People's Hospital Qujing Yunnan Province China
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40
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Su X, Peng D. Emerging functions of adipokines in linking the development of obesity and cardiovascular diseases. Mol Biol Rep 2020; 47:7991-8006. [PMID: 32888125 DOI: 10.1007/s11033-020-05732-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 08/18/2020] [Indexed: 12/19/2022]
Abstract
Increasing evidence shows that obesity is the critical factor in shaping cardio-metabolic phenotypes. However, the pathogenic mechanisms remain incompletely clarified. According to the published reports, adipose tissue communicates with several diverse organs, such as heart, lungs, and kidneys through the secretion of various cytokines named adipokines. The adipocytes isolated from obese mice or humans are dysfunctional with aberrant production of pro-inflammatory adipokines, which subsequently induce both acute and chronic inflammatory reaction and facilitate the process of cardio-metabolic disorder complications. Furthermore, the microenvironment within adipose tissue under obese status also influence the secretion of adipokines. Recently, given that several important adipokines have been completely researched and causally involved in various diseases, we could make a conclusion that adipokines play an essential role in modulating the development of cardio-metabolic disorder diseases, whereas several novel adipokines continue to be explored and elucidated. In the present review, we summarized the current knowledge of the microenvironment of adipose tissue and the published mechanisms whereby adipocytes affects obesity and cardiovascular diseases. On the other hand, we also provide the evidence to elucidate the functions of adipokines in controlling and regulating the inflammatory reactions which contribute to obesity and cardiovascular disease.
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Affiliation(s)
- Xin Su
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.,Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, Xiamen, Fujian, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
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41
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Obri A, Serra D, Herrero L, Mera P. The role of epigenetics in the development of obesity. Biochem Pharmacol 2020; 177:113973. [DOI: 10.1016/j.bcp.2020.113973] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/08/2020] [Indexed: 12/13/2022]
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42
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Jannat Ali Pour N, Meshkani R, Toolabi K, Mohassel Azadi S, Zand S, Emamgholipour S. Adipose tissue mRNA expression of HDAC1, HDAC3 and HDAC9 in obese women in relation to obesity indices and insulin resistance. Mol Biol Rep 2020; 47:3459-3468. [PMID: 32277440 DOI: 10.1007/s11033-020-05431-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/03/2020] [Indexed: 12/20/2022]
Abstract
It is well-established that an impaired adipose tissue function and morphology caused by a dysregulated gene expression contribute substantially to obesity. Nowadays, animal model studies and in vitro surveys provide evidence for possible roles of HDACs as emerging epigenetic players in the pathogenesis of obesity. However, the clinical pertinence of HDACs in the field of obesity research in humans is not yet obvious. Here, we investigated mRNA expression of HDAC1, 3 and 9 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of obese female participants (n = 20) and normal-weight women (n = 19). We also evaluated the association of the afore-mentioned HDACs gene expression with obesity indices, insulin resistance parameters, and other obesity-related characteristics. Our data revealed the mRNA level of HDAC1 was significantly decreased in both VAT and SAT of obese women, compared to controls. Moreover, the SAT mRNA expression of HDAC3 and VAT mRNA levels of HDAC9 were significantly lower in obese subjects than those found in controls. We observed that HDAC1 and HDAC3 expression in adipose tissue from the whole population is inversely correlated with obesity indices; BMI, waist, hip and waist-to-height ratio (WHtR). Moreover, we found that HDAC3 expression in adipose tissue had an inverse correlation with HOMA-IR, insulin levels, and serum concentration of hs-CRP. Moreover, VAT HDAC9 mRNA level is inversely correlated with obesity indices; BMI, waist, hip and WHtR and with HOMA-IR, insulin levels, and serum concentration of hs-CRP. Hence, it seems that decreased HDAC1,3 and 9 mRNA expression in adipose tissue might be associated with obesity and related abnormalities. However, more studies are needed to establish this concept.
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Affiliation(s)
- Naghmeh Jannat Ali Pour
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Karamollah Toolabi
- Department of Surgery, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Mohassel Azadi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahabedin Zand
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Solaleh Emamgholipour
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Hu S, Cho EH, Lee JY. Histone Deacetylase 9: Its Role in the Pathogenesis of Diabetes and Other Chronic Diseases. Diabetes Metab J 2020; 44:234-244. [PMID: 32347025 PMCID: PMC7188980 DOI: 10.4093/dmj.2019.0243] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 01/08/2020] [Indexed: 12/11/2022] Open
Abstract
As a member of the class IIa histone deacetylases (HDACs), HDAC9 catalyzes the deacetylation of histones and transcription factors, commonly leading to the suppression of gene transcription. The activity of HDAC9 is regulated transcriptionally and post-translationally. HDAC9 is known to play an essential role in regulating myocyte and adipocyte differentiation and cardiac muscle development. Also, recent studies have suggested that HDAC9 is involved in the pathogenesis of chronic diseases, including cardiovascular diseases, osteoporosis, autoimmune disease, cancer, obesity, insulin resistance, and liver fibrosis. HDAC9 modulates the expression of genes related to the pathogenesis of chronic diseases by altering chromatin structure in their promotor region or reducing the transcriptional activity of their respective transcription factors. This review summarizes the current knowledge of the regulation of HDAC9 expression and activity. Also, the roles of HDAC9 in the pathogenesis of chronic diseases are discussed, along with potential underlying mechanisms.
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Affiliation(s)
- Siqi Hu
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Eun Hee Cho
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Ji Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA.
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44
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Choi HI, Lee DH, Park SH, Jang YJ, Ahn J, Ha TY, Jung CH. Antiobesity effects of the combination of Patrinia scabiosaefolia root and Hippophae rhamnoides leaf extracts. J Food Biochem 2020; 44:e13214. [PMID: 32232876 DOI: 10.1111/jfbc.13214] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/02/2020] [Accepted: 02/24/2020] [Indexed: 12/21/2022]
Abstract
Patrinia scabiosaefolia (PS) and Hippophae rhamnoides (HR) are traditionally used functional foods. Extracts from the root of PS are known for their anti-inflammatory effects, whereas those from the leaf of HR are effective at both preventing and treating obesity. This study investigated whether the extract combination of PS and HR (PHE) affected weight loss in obese mice. In vitro experiments demonstrated that PHE showed a synergistic effect on inhibiting adipocyte differentiation as compared with treatment with the single extracts. Additionally, PHE suppressed adipogenic-related genes in a concentration-dependent manner. In vivo PHE supplementation suppressed body weight gain, inhibited hepatic lipid accumulation, decreased adipose size, serum triglycerides, and improved insulin resistance in obese mice. These results suggest that a treatment strategy using a combination of plant-derived extracts might be effective at ameliorating obesity. PRACTICAL APPLICATIONS: Currently, common methods for reducing obesity are diet and exercise. These can stimulate oxidative phosphorylation and metabolic activation so have significantly effects. However, these are largely due to individual compliance; there is no significant effect of reducing the worldwide obesity rate. Recently, herbal extracts has been reported as alternative medicine about inflammatory and obesity because diet with the herbal extracts can improve obesity with minimal side effects. Of particular, a mixture of herbal products was investigated for the treatment of obesity. Our reports demonstrated the synergistic effects of natural products and emphasizes the need for studies investigating other combinations of herbal extracts in the treatment of obesity. The results of our studies highlight the synergistic effects of combination phytochemical extracts and their role in ameliorating obesity.
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Affiliation(s)
- Hyun-Il Choi
- Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Da-Hye Lee
- Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Wanju-gun, Republic of Korea
| | - So-Hyun Park
- Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Wanju-gun, Republic of Korea
| | - Young-Jin Jang
- Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Jiyun Ahn
- Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Wanju-gun, Republic of Korea
| | - Tae-Youl Ha
- Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Wanju-gun, Republic of Korea
| | - Chang Hwa Jung
- Research Group of Natural Materials and Metabolism, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Wanju-gun, Republic of Korea
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Concise Review: The Regulatory Mechanism of Lysine Acetylation in Mesenchymal Stem Cell Differentiation. Stem Cells Int 2020; 2020:7618506. [PMID: 32399051 PMCID: PMC7204305 DOI: 10.1155/2020/7618506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 01/02/2020] [Indexed: 12/30/2022] Open
Abstract
Nowadays, the use of MSCs has attracted considerable attention in the global science and technology field, with the self-renewal and multidirectional differentiation potential for diabetes, obesity treatment, bone repair, nerve repair, myocardial repair, and so on. Epigenetics plays an important role in the regulation of mesenchymal stem cell differentiation, which has become a research hotspot in the medical field. This review focuses on the role of lysine acetylation modification on the determination of MSC differentiation direction. During this progress, the recruitment of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) is the crux of transcriptional mechanisms in the dynamic regulation of key genes controlling MSC multidirectional differentiation.
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46
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VDR regulates energy metabolism by modulating remodeling in adipose tissue. Eur J Pharmacol 2019; 865:172761. [DOI: 10.1016/j.ejphar.2019.172761] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/18/2019] [Accepted: 10/25/2019] [Indexed: 01/19/2023]
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Fan L, Ye H, Wan Y, Qin L, Zhu L, Su J, Zhu X, Zhang L, Miao Q, Zhang Q, Zhang Z, Xu A, Li Y, Li X, Wang Y. Adaptor protein APPL1 coordinates HDAC3 to modulate brown adipose tissue thermogenesis in mice. Metabolism 2019; 100:153955. [PMID: 31390528 DOI: 10.1016/j.metabol.2019.153955] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/12/2019] [Accepted: 07/31/2019] [Indexed: 01/17/2023]
Abstract
OBJECTIVES The activation of brown adipose tissue (BAT) is considered as a promising therapeutic target for obesity. APPL1 (Adaptor protein containing the Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif) is an intracellular adaptor protein and its genetic variation is correlated with BMI and body fat distribution in diabetic patients. However, little is known about the roles of APPL1 in BAT thermogenesis. MATERIALS/METHODS In this study, adipose tissue specific knockout (ASKO) mice were generated to evaluate APPL1's role in BAT thermogenesis in vivo, and possible signaling pathways were further explored in cultured brown adipocytes. RESULTS After high fat diet challenge, APPL1 ASKO mice developed more severe obesity, glucose intolerance and insulin resistance compared with control mice. Metabolic cage study showed that APPL1 deficiency impaired energy expenditure and adaptive thermogenesis in ASKO mice. PET-CT analysis showed decreased standardized uptake value (SUV) in the inter-scapular region which indicated impaired BAT activity in ASKO mice. Further study showed deletion of APPL1 attenuated brown fat specific gene expression, such as UCP1 and PGC1α in both BAT and brown adipocytes. In cultured brown adipocytes, upon cAMP stimulation, APPL1 shuttled from cytosol to nuclei. Co-IP and ChIP study showed that APPL1 could directly interact with histone deacetylase 3 (HDAC3) to mediate chromatin remodeling and UCP1 gene expression. CONCLUSIONS Our data demonstrated the essential role of APPL1 in regulating brown adipocytes thermogenesis via interaction with HDAC3, which may have potential therapeutic implications for treatment of obesity.
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Affiliation(s)
- Linling Fan
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Hongying Ye
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Yun Wan
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Lang Qin
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Zhu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Su
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaoming Zhu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Lv Zhang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Qing Miao
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiongyue Zhang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhaoyun Zhang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Aimin Xu
- Department of Medicine, the University of Hong Kong, Hong Kong
| | - Yiming Li
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Xi Li
- Institute of Life Sciences, Chongqing Medical University, China.
| | - Yi Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
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48
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Spracklen CN, Karaderi T, Yaghootkar H, Schurmann C, Fine RS, Kutalik Z, Preuss MH, Lu Y, Wittemans LBL, Adair LS, Allison M, Amin N, Auer PL, Bartz TM, Blüher M, Boehnke M, Borja JB, Bork-Jensen J, Broer L, Chasman DI, Chen YDI, Chirstofidou P, Demirkan A, van Duijn CM, Feitosa MF, Garcia ME, Graff M, Grallert H, Grarup N, Guo X, Haesser J, Hansen T, Harris TB, Highland HM, Hong J, Ikram MA, Ingelsson E, Jackson R, Jousilahti P, Kähönen M, Kizer JR, Kovacs P, Kriebel J, Laakso M, Lange LA, Lehtimäki T, Li J, Li-Gao R, Lind L, Luan J, Lyytikäinen LP, MacGregor S, Mackey DA, Mahajan A, Mangino M, Männistö S, McCarthy MI, McKnight B, Medina-Gomez C, Meigs JB, Molnos S, Mook-Kanamori D, Morris AP, de Mutsert R, Nalls MA, Nedeljkovic I, North KE, Pennell CE, Pradhan AD, Province MA, Raitakari OT, Raulerson CK, Reiner AP, Ridker PM, Ripatti S, Roberston N, Rotter JI, Salomaa V, Sandoval-Zárate AA, Sitlani CM, Spector TD, Strauch K, Stumvoll M, Taylor KD, Thuesen B, Tönjes A, Uitterlinden AG, Venturini C, Walker M, Wang CA, Wang S, Wareham NJ, Willems SM, Willems van Dijk K, Wilson JG, Wu Y, Yao J, Young KL, Langenberg C, Frayling TM, et alSpracklen CN, Karaderi T, Yaghootkar H, Schurmann C, Fine RS, Kutalik Z, Preuss MH, Lu Y, Wittemans LBL, Adair LS, Allison M, Amin N, Auer PL, Bartz TM, Blüher M, Boehnke M, Borja JB, Bork-Jensen J, Broer L, Chasman DI, Chen YDI, Chirstofidou P, Demirkan A, van Duijn CM, Feitosa MF, Garcia ME, Graff M, Grallert H, Grarup N, Guo X, Haesser J, Hansen T, Harris TB, Highland HM, Hong J, Ikram MA, Ingelsson E, Jackson R, Jousilahti P, Kähönen M, Kizer JR, Kovacs P, Kriebel J, Laakso M, Lange LA, Lehtimäki T, Li J, Li-Gao R, Lind L, Luan J, Lyytikäinen LP, MacGregor S, Mackey DA, Mahajan A, Mangino M, Männistö S, McCarthy MI, McKnight B, Medina-Gomez C, Meigs JB, Molnos S, Mook-Kanamori D, Morris AP, de Mutsert R, Nalls MA, Nedeljkovic I, North KE, Pennell CE, Pradhan AD, Province MA, Raitakari OT, Raulerson CK, Reiner AP, Ridker PM, Ripatti S, Roberston N, Rotter JI, Salomaa V, Sandoval-Zárate AA, Sitlani CM, Spector TD, Strauch K, Stumvoll M, Taylor KD, Thuesen B, Tönjes A, Uitterlinden AG, Venturini C, Walker M, Wang CA, Wang S, Wareham NJ, Willems SM, Willems van Dijk K, Wilson JG, Wu Y, Yao J, Young KL, Langenberg C, Frayling TM, Kilpeläinen TO, Lindgren CM, Loos RJF, Mohlke KL. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology. Am J Hum Genet 2019; 105:15-28. [PMID: 31178129 DOI: 10.1016/j.ajhg.2019.05.002] [Show More Authors] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 04/30/2019] [Indexed: 12/25/2022] Open
Abstract
Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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Affiliation(s)
- Cassandra N Spracklen
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Tugce Karaderi
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; DTU Health Technology, Technical University of Denmark, Lyngby 2800, Denmark
| | - Hanieh Yaghootkar
- Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK; Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK
| | - Claudia Schurmann
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rebecca S Fine
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Zoltan Kutalik
- Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK; University Center for Primary Care and Public Health, University of Lausanne, Lausanne 1010, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland
| | - Michael H Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yingchang Lu
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN 37203-1738, USA; Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Laura B L Wittemans
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Linda S Adair
- Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA
| | - Matthew Allison
- Department of Family Medicine and Public Health, University of California, San Diego, CA 92093, USA
| | - Najaf Amin
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
| | - Paul L Auer
- Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
| | - Traci M Bartz
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Biostatistics, University of Washington, Seattle, WA 98101, USA
| | - Matthias Blüher
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 4103, Germany
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Judith B Borja
- Office of Population Studies Foundation, Inc, Cebu City, Philippines; Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines
| | - Jette Bork-Jensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Linda Broer
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands
| | - Daniel I Chasman
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Yii-Der Ida Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Paraskevi Chirstofidou
- Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
| | - Ayse Demirkan
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
| | - Cornelia M van Duijn
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
| | - Mary F Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Melissa E Garcia
- National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
| | - Mariaelisa Graff
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, Chapel Hill, NC 27599, USA
| | - Harald Grallert
- Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, München-Neuherberg 85764, Germany; German Center for Diabetes Research, München-Neuherberg 85765, Germany
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Jeffrey Haesser
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Tamara B Harris
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA
| | - Heather M Highland
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jaeyoung Hong
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 2118, USA
| | - M Arfan Ikram
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands
| | - Erik Ingelsson
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA 94304, USA; Stanford Cardiovascular Institute, Stanford University of Medicine, Palo Alto, CA 94304, USA; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA
| | - Rebecca Jackson
- Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH 43210, USA
| | - Pekka Jousilahti
- Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki 00271, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere 33522, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33522, Finland
| | - Jorge R Kizer
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Peter Kovacs
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 4103, Germany
| | - Jennifer Kriebel
- Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, München-Neuherberg 85764, Germany; German Center for Diabetes Research, München-Neuherberg 85765, Germany
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University of Hospital, Kuopio 70029 KYS, Finland
| | - Leslie A Lange
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Denver, CO 80045, USA
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33522, Finland
| | - Jin Li
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala 75185, Sweden
| | - Jian'an Luan
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33522, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33521, Finland
| | - Stuart MacGregor
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - David A Mackey
- Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA 6009, Australia; Centre for Ophthalmology and Visual Science, Lions Eye Institute, The University of Western Australia, Perth, WA 6009, Australia
| | - Anubha Mahajan
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
| | - Massimo Mangino
- Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' Foundation Trust, London SE1 9RT, UK
| | - Satu Männistö
- Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki 00271, Finland
| | - Mark I McCarthy
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford OX3 7FZ, UK
| | - Barbara McKnight
- Department of Biostatistics, University of Washington, Seattle, WA 98101, USA
| | - Carolina Medina-Gomez
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands
| | - James B Meigs
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Population and Medical Genetics, Broad Institute, Cambridge, MA 02114, USA
| | - Sophie Molnos
- Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, München-Neuherberg 85764, Germany; German Center for Diabetes Research, München-Neuherberg 85765, Germany
| | - Dennis Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden 2334 ZA, the Netherlands
| | - Andrew P Morris
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK
| | - Renee de Mutsert
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands
| | - Mike A Nalls
- Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD 20812, USA
| | - Ivana Nedeljkovic
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
| | - Kari E North
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Craig E Pennell
- School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW 2305, Australia
| | - Aruna D Pradhan
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Michael A Province
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Olli T Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
| | - Chelsea K Raulerson
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Alex P Reiner
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Paul M Ridker
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Samuli Ripatti
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Public Health, University of Helsinki, Helsinki 00014, Finland; Institute for Molecular Medicine Finland, Helsinki 00014, Finland
| | - Neil Roberston
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Veikko Salomaa
- Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki 00271, Finland
| | | | - Colleen M Sitlani
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
| | - Tim D Spector
- Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
| | - Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany; Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich 81377, Germany
| | - Michael Stumvoll
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 4103, Germany
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Betina Thuesen
- Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen 2400, Denmark
| | - Anke Tönjes
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig, Leipzig 4103, Germany
| | - Andre G Uitterlinden
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands
| | - Cristina Venturini
- Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
| | - Mark Walker
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, UK
| | - Carol A Wang
- School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW 2305, Australia
| | - Shuai Wang
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 2118, USA
| | | | - Sara M Willems
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Ko Willems van Dijk
- Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden 2333 ZA, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands
| | - James G Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Ying Wu
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jie Yao
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Kristin L Young
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Timothy M Frayling
- Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK
| | - Tuomas O Kilpeläinen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Cecilia M Lindgren
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7FZ, UK; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF, UK
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Karen L Mohlke
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Bagchi RA, Weeks KL. Histone deacetylases in cardiovascular and metabolic diseases. J Mol Cell Cardiol 2019; 130:151-159. [PMID: 30978343 DOI: 10.1016/j.yjmcc.2019.04.003] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 03/29/2019] [Accepted: 04/06/2019] [Indexed: 12/13/2022]
Abstract
Histone deacetylases (HDACs) regulate gene transcription by catalyzing the removal of acetyl groups from key lysine residues in nucleosomal histones and via the recruitment of other epigenetic regulators to DNA promoter/enhancer regions. Over the past two decades, HDACs have been implicated in multiple processes pertinent to cardiovascular and metabolic diseases, including cardiac hypertrophy and remodeling, fibrosis, calcium handling, inflammation and energy metabolism. The development of small molecule HDAC inhibitors and genetically modified loss- and gain-of-function mouse models has allowed interrogation of the roles of specific HDAC isoforms in these processes. Isoform-selective HDAC inhibitors may prove to be powerful therapeutic agents for the treatment of cardiovascular diseases, obesity and diabetes.
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Affiliation(s)
- Rushita A Bagchi
- Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Kate L Weeks
- Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC 3800, Australia.
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50
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Meng Y, Cui Y, Zhang W, Fu S, Huang L, Dong H, Du H. Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats. Front Genet 2019; 9:724. [PMID: 30687391 PMCID: PMC6335273 DOI: 10.3389/fgene.2018.00724] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/22/2018] [Indexed: 12/18/2022] Open
Abstract
The Goto Kakizaki (GK) rats which can spontaneously develop type 2 diabetes (T2D), are generated by repeated inbreeding of Wistar rats with glucose intolerance. The glucose intolerance in GK rat is mainly attributed to the impairment in glucose-stimulated insulin secretion (GSIS). In addition, GK rat display a decrease in beta cell mass, and a change in insulin action. However, the genetic mechanism of these features remain unclear. In the present study, we analyzed the population variants of GK rats and control Wistar rats by whole genome sequencing and identified 1,839 and 1,333 specific amino acid changed (SAAC) genes in GK and Wistar rats, respectively. We also detected the putative artificial selective sweeps (PASS) regions in GK rat which were enriched with GK fixed variants and were under selected in the initial diabetic-driven derivation by homogeneity test with the fixed and polymorphic sites between GK and Wistar populations. Finally, we integrated the SAAC genes, PASS region genes and differentially expressed genes in GK pancreatic beta cells to reveal the genetic mechanism of the impairment in GSIS, a decrease in beta cell mass, and a change in insulin action in GK rat. The results showed that Slc2a2 gene was related to impaired glucose transport and Adcy3, Cacna1f, Bmp4, Fam3b, and Ptprn2 genes were related to Ca2+ channel dysfunction which may responsible for the impaired GSIS. The genes Hnf4g, Bmp4, and Bad were associated with beta cell development and may be responsible for a decrease in beta cell mass while genes Ide, Ppp1r3c, Hdac9, Ghsr, and Gckr may be responsible for the change in insulin action in GK rats. The overexpression or inhibition of Bmp4, Fam3b, Ptprn2, Ide, Hnf4g, and Bad has been reported to change the glucose tolerance in rodents. However, the genes Bmp4, Fam3b, and Ptprn2 were found to be associated with diabetes in GK rats for the first time in the present study. Our findings provide a comprehensive genetic map of the abnormalities in GK genome which will be helpful in understand the underlying genetic mechanism of pathogenesis of diabetes in GK rats.
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Affiliation(s)
- Yuhuan Meng
- School of Biology and Biological Engineering - Department of Biomedical Engineering, South China University of Technology, Guangzhou, China
| | - Ying Cui
- School of Biology and Biological Engineering - Department of Biomedical Engineering, South China University of Technology, Guangzhou, China
| | - Wenlu Zhang
- School of Biology and Biological Engineering - Department of Biomedical Engineering, South China University of Technology, Guangzhou, China
| | - Shuying Fu
- School of Biology and Biological Engineering - Department of Biomedical Engineering, South China University of Technology, Guangzhou, China
| | - Lizhen Huang
- School of Biology and Biological Engineering - Department of Biomedical Engineering, South China University of Technology, Guangzhou, China
| | - Hua Dong
- School of Biology and Biological Engineering - Department of Biomedical Engineering, South China University of Technology, Guangzhou, China
| | - Hongli Du
- School of Biology and Biological Engineering - Department of Biomedical Engineering, South China University of Technology, Guangzhou, China
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