Abstract
Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.
Highlights
Fat distribution is an independent cardiometabolic risk factor
genomewide association study (GWAS) results have identified associations between at least two independent signals at RSPO3 and WHRadjBMI12. Associations at both the sentinel and secondary single-nucleotide variants (SNVs) were stronger in females. We extended these findings by mining genotype and dual-energy X-ray absorptiometry (DXA) data from over 4500 adults from the Oxford Biobank (OBB) (Table 1)
We found that the WHRadjBMIincreasing alleles at both rs72959041 and rs9491696 were associated with a redistribution of fat from the lower- to the upperbody, which appeared to be driven by a reduction in leg fat mass at both signals and a concomitant increase in android fat mass at rs72959041 (Table 1)
Summary
Fat distribution is an independent cardiometabolic risk factor. its molecular and cellular underpinnings remain obscure. It is established that different fat depots arise from unique APs with distinct biological properties and developmental gene expression signatures[2,7,8,9,10], which give rise to specialised adipocytes with diverse functional traits These findings have led to the hypothesis that developmental pathways play a critical role in establishing AP and adipocyte identity and in determining the size of fat depots, by modulating adipocyte number and size in each depot. Consistent with this theory, annotation of genomewide association study (GWAS) meta-data revealed enrichment for developmental genes at loci influencing waist-hip ratio adjusted for BMI (WHRadjBMI), a surrogate measure of fat distribution[11]. Genetic variants at the RSPO3 locus were shown to be the strongest genetic determinants of WHRadjBMI12 the causal variants, cis-effector gene (s) and target tissue(s) at this locus have not been mapped
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