Loss of Mbd2 Protects Mice Against High-Fat Diet–Induced Obesity and Insulin Resistance by Regulating the Homeostasis of Energy Storage and Expenditure

Abstract

Previous studies including ours demonstrated that methyl-CpG-binding domain 2 (MBD2) acts as a reader to decipher DNA methylome-encoded information. We thus in the current study used Mbd2 mice as a model to dissect the impact of high-fat diet (HFD) on DNA methylome relevant to the pathoetiology of obesity. It was interestingly noted that mice deficient in Mbd2 were protected from HFD-induced obesity and insulin resistance. Mechanistic study revealed that HFD rendered epididymal adipose tissues to undergo a DNA methylation turnover as evidenced by the changes of methylation levels and patterns. Specifically, HFD was noted with higher potency to induce DNA hypomethylation in genes relevant to energy storage than that in genes associated with energy expenditure. As a result, arrays of genes were subjected to expression changes, which led to an altered homeostasis for energy storage and expenditure in favor of obesity development. Loss of Mbd2 resulted in impaired implementation of above DNA methylation changes associated with altered energy homeostasis, which then protected mice from HFD-induced obesity and insulin resistance. Those data would provide novel insight into the understanding of the pathoetiology underlying obesity with potential for developing effective therapies against obesity in clinical settings.

Deciphering GRINA/Lifeguard1: Nuclear Location, Ca2+ Homeostasis and Vesicle Transport

“…Methyl-CpG binding domain protein 2 (MBD2) is upregulated at specific stages of spermatogenesis [106] and required for correct spatial gene expression in the gut [107]. Its loss protects mice against high-fat diet-induced obesity and insulin resistance [108]. Inhibitor of DNA binding 4 (ID4) is up-regulated during embryogenesis and its highest expression in adult mice occurs in testes, brain and kidneys [109].…”

“…Methyl-CpG binding domain protein 2 (MBD2) is upregulated at specific stages of spermatogenesis [106] and required for correct spatial gene expression in the gut [107]. Its loss protects mice against high-fat diet-induced obesity and insulin resistance [108].…”

Physical exercise, gut, gut microbiota, and atherosclerotic cardiovascular diseases

“…Short-chain fatty acids (SCFAs) are the major end products from the microbial degradation of carbohydrates and protein in the gut. The majority of SCFAs are absorbed from the gut and metabolized in various body tissues, contributing to some important physiological processes, especially effects daily energy requirements [ 12 , 13 ].…”

DNA methylation landscapes in the pathogenesis of type 2 diabetes mellitus

“…Another genome-wide DNA methylation research revealed that patients were predisposed to insulin resistance and T2DM with aberrant DNA methylation in the visceral adipose tissue [ 51 ]. Recently, study by Cheng et al discovered that loss of methyl-CpG-binding domain 2 (MBD2) resulted in DNA methylation changes associated with altered energy homeostasis, which protected mice from HFD-induced obesity and insulin resistance [ 52 ].…”