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, Jae Bum Kim

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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.

Original languageEnglish
Article number7585
JournalNature Communications
Volume6
DOIs
StatePublished - 3 Jul 2015

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obesity
insulin
Adiponectin
genes
Insulin Resistance
deoxyribonucleic acid
Obesity
Genes
Insulin
DNA
homeostasis
glucose
metabolic diseases
lipid metabolism
chromatin
Epigenomics
metabolism
Homeostasis
inhibitors
Glucose

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Kim, A. Young ; Park, Yoon Jeong ; Pan, Xuebo ; Shin, Kyung Cheul ; Kwak, Soo Heon ; Bassas, Abdulelah F. ; Sallam, Reem M. ; Park, Kyong Soo ; Alfadda, Assim A. ; Xu, Aimin ; Kim, Jae Bum. / Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance. In: Nature Communications. 2015 ; Vol. 6.
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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.",
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Kim, AY, Park, YJ, Pan, X, Shin, KC, Kwak, SH, Bassas, AF, Sallam, RM, Park, KS, Alfadda, AA, Xu, A & Kim, JB 2015, 'Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance', Nature Communications, vol. 6, 7585. https://doi.org/10.1038/ncomms8585

Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance. / Kim, A. Young; Park, Yoon Jeong; Pan, Xuebo; Shin, Kyung Cheul; Kwak, Soo Heon; Bassas, Abdulelah F.; Sallam, Reem M.; Park, Kyong Soo; Alfadda, Assim A.; Xu, Aimin; Kim, Jae Bum.

In: Nature Communications, Vol. 6, 7585, 03.07.2015.

Research output: Contribution to journalArticle

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