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

Nat Commun. 2015 Jul 3;6:7585. doi: 10.1038/ncomms8585.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adiponectin / genetics*
  • Adipose Tissue / metabolism
  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Cytokines / metabolism*
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Humans
  • Inflammation
  • Insulin Resistance / genetics*
  • Mice
  • Obesity / genetics*
  • Obesity / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Leptin / genetics


  • ADIPOQ protein, human
  • Adiponectin
  • Adipoq protein, mouse
  • Cytokines
  • RNA, Messenger
  • Receptors, Leptin
  • leptin receptor, mouse
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Dnmt1 protein, mouse