Abstract
Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for the hydrolysis of triacylglycerols stored in adipocytes. To increase our understanding of the genetic regulation of body fat distribution and total body fat, we set out to determine if genetic variants associated with body mass index (BMI) or waist-hip-ratio adjusted for BMI (WHRadjBMI) in genome-wide association studies (GWAS) mediate their effect by influencing adipocyte lipolysis. We utilized data from the recent GWAS of spontaneous and isoprenaline-stimulated lipolysis in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort. GENiAL consists of 939 participants who have undergone abdominal subcutaneous adipose biopsy for the determination of spontaneous and isoprenaline-stimulated lipolysis in adipocytes. We report 11 BMI and 15 WHRadjBMI loci with SNPs displaying nominal association with lipolysis and allele-dependent gene expression in adipose tissue according to in silico analysis. Functional evaluation of candidate genes in these loci by small interfering RNAs (siRNA)-mediated knock-down in adipose-derived stem cells identified ZNF436 and NUP85 as intrinsic regulators of lipolysis consistent with the associations observed in the clinical cohorts. Furthermore, candidate genes in another BMI-locus (STX17) and two more WHRadjBMI loci (NID2, GGA3, GRB2) control lipolysis alone, or in conjunction with lipid storage, and may hereby be involved in genetic control of body fat. The findings expand our understanding of how genetic variants mediate their impact on the complex traits of fat storage and distribution.
Highlights
Materials and methodsThe GENiAL cohort and genome-wide association studies (GWAS) of abdominal subcutaneous adipose tissue (SAT) lipolysis have been described p reviously[8]
Eight of the latter SNPs demonstrated expression quantitative trait locus (eQTL) in subcutaneous adipose tissue (SAT) according to GTEx (Table 1)
Among index-SNPs in 346 genetic loci associated with W HRadjBMI1, 12 displayed nominal associations (p < 0.05) with spontaneous lipolysis; eight of these SNPs demonstrated eQTLs in SAT according to GTEx (Table 2, Supplementary 4). 20 SNPs displayed associations with WHRadjBMI and isoprenaline-stimulated lipolysis (Supplementary Table 5) of which ten SNPs were eQTLs in SAT (Table 2)
Summary
The GENiAL cohort and GWAS of abdominal subcutaneous adipose tissue (SAT) lipolysis have been described p reviously[8]. Adipocyte lipolysis in clinical samples were measured as previously described[8]. Spontaneous lipolysis was expressed as glycerol release/cell weight multiplied by the estimated abdominal subcutaneous fat mass, i.e., an estimate of the total release of glycerol from the area which is the site for the biopsy[8]. The genetic analysis of spontaneous and stimulated lipolysis in GENiAL was performed in PLINK using linear regression, assuming an additive genetic model and including age, sex and BMI as covariates[8]. SNPs that were identified as being shared loci (GWAS-significant loci for BMI or WHRadjBMI and nominally significant (p < 0.05) for basal or stimulated lipolysis) were used as the exposure. Differentiation to adipocytes was started by medium replacement 24 h post-transfection and medium was subsequently replaced every third day
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