title: Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance.
abstract: Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.
authors.affiliation: Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea.
authors.forename: A Young
authors.initials: AY
authors.lastname: Kim
authors.affiliation: 1] Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea [2] Department of Biophysics and Chemical Biology, Seoul National University, Seoul 151-742, Korea.
authors.forename: Yoon Jeong
authors.initials: YJ
authors.lastname: Park
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Pan
authors.affiliation: 1] Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea [2] School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Kyung Cheul
authors.initials: KC
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Soo-Heon
authors.initials: SH
authors.lastname: Kwak
authors.affiliation: Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
authors.forename: Abdulelah F
authors.initials: AF
authors.lastname: Bassas
authors.affiliation: Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
authors.forename: Reem M
authors.identifier: 0000000258144811
authors.initials: RM
authors.lastname: Sallam
authors.affiliation: 1] Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea [2] Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 110-799, Korea.
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.affiliation: 1] Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia [2] Department of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
authors.forename: Assim A
authors.initials: AA
authors.lastname: Alfadda
authors.affiliation: 1] State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China [2] Department of Medicine, The University of Hong Kong, Hong Kong, China [3] Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: 1] Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea [2] School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
mesh_terms: D041721:3T3-L1 Cells; D052242:Adiponectin / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D054411:Receptors, Leptin / Q000235:genetics
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D016207:Cytokines; D012333:RNA, Messenger; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse