WHRadjBMI-increasing alleles at the RSPO3 locus increase RSPO3 expression in subcutaneous adipocytes, leading to reduced lower-body fat and enlarged gluteal adipocytes.
RSPO3 is a key determinant of peripheral adipose tissue storage capacity, regulating body fat distribution through depot-specific effects on adipocyte biology.
Effect estimate: β 0.05
p-value: p=3×10^-8
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.
Loh et al. (Wed,) conducted a other in Body fat distribution (n=4,571). RSPO3 WHRadjBMI-increasing alleles vs. Ancestral alleles was evaluated on Android/gynoid fat ratio (β 0.05, p=3×10^-8). WHRadjBMI-increasing alleles at the RSPO3 locus increase RSPO3 expression in subcutaneous adipocytes, leading to reduced lower-body fat and enlarged gluteal adipocytes.