Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance

A. Young Kim, Yoon Jeong Park, Xuebo Pan, Kyung Cheul Shin, Soo-Heon Kwak, Abdulelah F. Bassas, Reem M. Sallam, Kyong Soo Park, Assim A. Alfadda, Aimin Xu and Jae Bum Kim ()
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A. Young Kim: Institute of Molecular Biology and Genetics, Seoul National University
Yoon Jeong Park: Institute of Molecular Biology and Genetics, Seoul National University
Xuebo Pan: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
Kyung Cheul Shin: Institute of Molecular Biology and Genetics, Seoul National University
Soo-Heon Kwak: Seoul National University College of Medicine
Abdulelah F. Bassas: Obesity Research Center, College of Medicine, King Saud University
Reem M. Sallam: Obesity Research Center, College of Medicine, King Saud University
Kyong Soo Park: Seoul National University College of Medicine
Assim A. Alfadda: Obesity Research Center, College of Medicine, King Saud University
Aimin Xu: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
Jae Bum Kim: Institute of Molecular Biology and Genetics, Seoul National University

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8585

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