Genetics and epigenetics in the obesity phenotyping scenario

Abstract

Obesity is a common complex trait that elevates the risk for various diseases, including type 2 diabetes and cardiovascular disease. A combination of environmental and genetic factors influences the pathogenesis of obesity. Advances in genomic technologies have driven the identification of multiple genetic loci associated with this disease, ranging from studying severe onset cases to investigating common multifactorial polygenic forms. Additionally, findings from epigenetic analyses of modifications to the genome that do not involve changes to the underlying DNA sequence have emerged as key signatures in the development of obesity. Such modifications can mediate the effects of environmental factors, including diet and lifestyle, on gene expression and clinical presentation. This review outlines what is known about the genetic and epigenetic contributors to obesity susceptibility, along with the albeit limited therapeutic options currently available. Furthermore, we delineate the potential mechanisms of actions through which epigenetic changes can mediate environmental influences and the related opportunities they present for future interventions in the management of obesity.

Keywords: Epigenetics; GWAS; Genetics; Genomics; Monogenic; Obesity; Polygenic.

Fig. 1

Leptin-melanocortin pathway. Leptin is an anorexigenic hormone produced by white adipocytes, with its levels driven by the degree of fat mass present, and influences food consumption together with energy balance [112]. When its circulating levels become lower in the fasting state and rise when feeding takes place, leptin influences appetite via the hypothalamus [113, 114]. The arcuate nucleus is a component of the hypothalamus, where a key isoform of leptin receptor resides in two types of neurons, one expressing POMC and the other expressing agouti-related protein (AGRP) [115]. Leptin stimulates neurons expressing POMC, which is subsequently processed to various active melanocortin peptides [116]. The POMC-expressing neurons contact MC4R neurons in the paraventricular nucleus (PVN) where these melanocortin peptides influence a reduction in intake of food [115], whereas AGRP antagonizes MC4R to do the opposite [115, 117]; as such representing a finely tuned balance in the regulation of appetite

Fig. 2

Four functional follow-up strategies of different GWAS-implicated obesity loci. (A). A specific variant embedded within the FTO gene is located in an ARID5B regulatory element, which in turn impacts the expression of the neighboring genes, IRX3 and IRX5, which play a role in adipose biology [150]. (B). One of the strongest obesity loci coincides with the TMEM18 gene [151, 152], which encodes a poorly characterized transmembrane protein. Work with a Drosophila melanogaster knock-out model implicates TMEM18 in influencing lipid and carbohydrate levels via disruption of insulin and glucagon signaling [153], while knock-out in a mouse model leads to increased body weight due to elevated food intake, with over-expression of the gene showing an opposite effect [154]. (C). CADM1 and CADM2 encode cell-adhesion proteins in the brain. The associated variants influence the expression of the respective genes in the hypothalamus, leading to increased body weight, insulin sensitivity and energy expenditure. Loss of function of these genes promotes weight loss. Keto diet (“green” food cube) showed lower expression of these genes and promoted weight loss [155, 156]. (D). Deletion variants located just upstream of NEGR1 impacts a binding site for the strong transcriptional repressor NKX6.1. When NKX6.1 binding is lost, increased NEGR1 expression is observed. NEGR1 is expressed in the brain. Studies in mice have found that NEGR1 deficiency lowers body weight via a reduction in lean mass [157], although other studies have found opposite results [158, 159]. High-fat diet seemed to accelerate weight loss.

Fig. 3

Genes affected by environmental factors through epigenetic mechanisms. Genes are color-coded by mechanism. The genes within each section are specific for each factor, and genes placed in the middle space are common between at least two factors