Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance.
A Young KimYoon Jeong ParkXuebo PanKyung Cheul ShinSoo-Heon KwakAbdulelah F BassasReem M SallamKyong Soo ParkAssim A AlfaddaAimin XuJae Bum KimPublished in: Nature communications (2015)
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.
Keyphrases
- insulin resistance
- metabolic syndrome
- dna methylation
- high fat diet induced
- adipose tissue
- high fat diet
- skeletal muscle
- genome wide
- polycystic ovary syndrome
- poor prognosis
- type diabetes
- gene expression
- high glucose
- signaling pathway
- weight loss
- drug induced
- weight gain
- binding protein
- body mass index
- physical activity
- cell free
- single molecule
- blood glucose
- nitric oxide
- endothelial cells
- sensitive detection
- smoking cessation
- living cells
- genome wide analysis