Genetics and epigenetics of obesity

Abstract

Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40-70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or "imprinting", affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader-Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity.

Fig. 1

CpG methylation and regulation of gene expression. Unmethylated or hypomethylated DNA (usually in the promoter region) allows binding of the transcription factors (TF) and other regulatory mechanisms which results in transcription and mRNA production. Methylated DNA (bottom panel) obstructs binding of the TF, and in some cases might recruit methyl-CpG binding proteins and other transcription co-repressors, blocking access of the transcription enzymes and resulting in gene silencing.

Fig. 2

Histone modification. This simplified diagram of a nucleosome shows a histone octamer “bead” surrounded by a DNA strand and try-methylation at lysine-9, this kind of modification exemplifies modifications found at promoter regions of silenced genes.