The genetics of fat distribution

Abstract

Fat stored in visceral depots makes obese individuals more prone to complications than subcutaneous fat. There is good evidence that body fat distribution (FD) is controlled by genetic factors. WHR, a surrogate measure of FD, shows significant heritability of up to ∼60%, even after adjusting for BMI. Genetic variants have been linked to various forms of altered FD such as lipodystrophies; however, the polygenic background of visceral obesity has only been sparsely investigated in the past. Recent genome-wide association studies (GWAS) for measures of FD revealed numerous loci harbouring genes potentially regulating FD. In addition, genes with fat depot-specific expression patterns (in particular subcutaneous vs visceral adipose tissue) provide plausible candidate genes involved in the regulation of FD. Many of these genes are differentially expressed in various fat compartments and correlate with obesity-related traits, thus further supporting their role as potential mediators of metabolic alterations associated with a distinct FD. Finally, developmental genes may at a very early stage determine specific FD in later life. Indeed, genes such as TBX15 not only manifest differential expression in various fat depots, but also correlate with obesity and related traits. Moreover, recent GWAS identified several polymorphisms in developmental genes (including TBX15, HOXC13, RSPO3 and CPEB4) strongly associated with FD. More accurate methods, including cardiometabolic imaging, for assessment of FD are needed to promote our understanding in this field, where the main focus is now to unravel the yet unknown biological function of these novel 'fat distribution genes'.

Adipokines in health and disease

“…Adipocyte hypertrophy most likely initiates alterations in adipose tissue, which predisposes adipose tissue to immune cell infiltration and an adverse (proinflammatory, diabetogenic, and atherogenic) adipokine secretion pattern [4]. In addition, adipokine secretion may be influenced by fat distribution or may contribute to distinct fat distribution subtypes [18]. Several adipokines, including leptin, IL-6 [19], RBP4 [20], chemerin [21], progranulin [22], and others, are differentially expressed in various fat compartments and correlate with obesityrelated traits, further supporting their role as potential mediators of metabolic alterations associated with a distinct fat distribution [18,23].…”

From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century

“…Visceral fat distribution is clearly a stronger predictor for obesity related metabolic and cardiovascular diseases as whole body fat mass or BMI [4,60,61]. However, quantification of total visceral fat mass requires sophisticated and expensive imaging techniques.…”

“…Recently, several members of the BMP family of ligands and receptors have been found to associate with obesity-related traits in humans [61,197,198].…”

Numerous Genes in Loci Associated With Body Fat Distribution Are Linked to Adipose Function

“…Central body fat accumulation is governed by genetic factors (1) and is, independently of total adiposity, associated with metabolic conditions such as type 2 diabetes and cardiovascular disease (2). A recent genome-wide association (GWA) meta-analysis identified 68 genetic loci that associate with body fat distribution, primarily waist-to-hip ratio (WHR) but also related traits such as waist circumference (3).…”