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Minghong Jiang, Yuhao Zhang, Meng Liu, Michael Shihli Lan, Jing Fei, Weiwei Fan, Xin Gao, Daru Lu, Hypermethylation of Hepatic Glucokinase and L-Type Pyruvate Kinase Promoters in High-Fat Diet–Induced Obese Rats, Endocrinology, Volume 152, Issue 4, 1 April 2011, Pages 1284–1289, https://doi.org/10.1210/en.2010-1162
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Abstract
Obesity-dependent insulin resistance and type 2 diabetes mellitus are closely associated with decreased glucose utilization and down-regulation of hepatic glycolytic enzymes expression. Previously, we showed that DNA hypermethylation is involved in age-dependent susceptibility to hepatic insulin resistance and diabetes. However, what we cannot distinguish is whether the age-related obesity contributes to DNA hypermethylation in those natural aging rats. In the present study, we hypothesize that DNA methylation plays a crucial role in the regulation of glycolytic enzymes in the high-fat diet–induced obesity. Here, we report that DNA hypermethylation is correlated with a decline in hepatic glucokinase (Gck) and L-type pyruvate kinase (LPK) expression in high-fat diet–induced obese rats as compared with the control diet group. Down-regulation of Gck and LPK expression are reversed by the 5-aza-2′-deoxycytidine in the cell model of steatosis. These novel observations indicate that DNA methylation is involved in the development of metabolic diseases, such as obesity, insulin resistance, type 2 diabetes mellitus, and nonalcoholic steatohepatitis, suggesting that the hypermethylation level of Gck and LPK promoters may be a useful parameter for the evaluation of obesity-induced insulin resistance and fatty liver.