Abstract
ObjectivesNumerous genetic loci have been associated with measures of central fat accumulation, such as waist-to-hip ratio adjusted for body mass index (WHRadjBMI). However the mechanisms by which genetic variations influence obesity remain largely elusive. Lipolysis is a key process for regulation of lipid storage in adipocytes, thus is implicated in obesity and its metabolic complications. Here, genetic variants at 36 WHRadjBMI-associated loci were examined for their influence on abdominal subcutaneous adipocyte lipolysis.Subjects and MethodsFasting subcutaneous adipose tissue biopsies were collected from 789 volunteers (587 women and 202 men, body mass index (BMI) range 17.7–62.3 kg/m2). We quantified subcutaneous adipocyte lipolysis, both spontaneous and stimulated by the catecholamine isoprenaline or a cyclic AMP analogue. DNA was extracted from peripheral blood mononuclear cells and genotyping of SNPs associated with WHRadjBMI conducted. The effects on adipocyte lipolysis measures were assessed for SNPs individually and combined in a SNP score.ResultsThe WHRadjBMI-associated loci CMIP, PLXND1, VEGFA and ZNRF3-KREMEN1 demonstrated nominal associations with spontaneous and/or stimulated lipolysis. Candidate genes in these loci have been reported to influence NFκB-signaling, fat cell size and Wnt signalling, all of which may influence lipolysis.SignificanceThis report provides evidence for specific WHRadjBMI-associated loci as candidates to modulate adipocyte lipolysis. Additionally, our data suggests that genetically increased central fat accumulation is unlikely to be a major cause of altered lipolysis in abdominal adipocytes.
Highlights
With an almost epidemic global increase in obesity [1], related complications including type 2 diabetes and cardiovascular disease are a growing burden on healthcare systems
waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI) can be considered as a measure of fat distribution independent of overall obesity [4]
Recent genome wide association studies (GWAS) have identified several genetic loci associated with WHRadjBMI [4,5,6]
Summary
With an almost epidemic global increase in obesity [1], related complications including type 2 diabetes and cardiovascular disease are a growing burden on healthcare systems. Central fat accumulation, reflected by high waist-to-hip ratio (WHR), is strongly associated with risk for type 2 diabetes and other complications [3]. Recent genome wide association studies (GWAS) have identified several genetic loci associated with WHRadjBMI [4,5,6]. These findings notwithstanding, the identity of both the culprit genes in the loci and the mechanisms by which they influence adipose function or clinical phenotypes remain unclear. Whereas central regulation of food intake is believed to be a major determinant of overall obesity and BMI [7], it seems likely that fat distribution, as assessed by WHR, is primarily regulated locally in adipose tissue. A few genes at these loci have recently been shown to be differentially expressed between subcutaneous and visceral adipose tissue compatible with a depot specific function [8]
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