RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro
- Loh, N.Y., Minchin, J.E.N., Pinnick, K.E., Verma, M., Todorčević, M., Denton, N., Moustafa, J.E., Kemp, J.P., Gregson, C.L., Evans, D.M., Neville, M.J., Small, K.S., McCarthy, M.I., Mahajan, A., Rawls, J.F., Karpe, F., Christodoulides, C.
- Nature communications 11: 2797 (Journal)
- Registered Authors
- Minchin, James, Rawls, John F.
- MeSH Terms
- Adipocytes/drug effects
- Adipose Tissue/metabolism
- Body Fat Distribution*
- Cell Differentiation/drug effects
- Cell Line
- Cell Size/drug effects
- Gene Expression Regulation/drug effects
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism*
- Middle Aged
- Polymorphism, Single Nucleotide/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Sex Characteristics
- Stem Cells/metabolism
- Waist-Hip Ratio
- Wnt Signaling Pathway/drug effects
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 32493999 Full text @ Nat. Commun.
Loh, N.Y., Minchin, J.E.N., Pinnick, K.E., Verma, M., Todorčević, M., Denton, N., Moustafa, J.E., Kemp, J.P., Gregson, C.L., Evans, D.M., Neville, M.J., Small, K.S., McCarthy, M.I., Mahajan, A., Rawls, J.F., Karpe, F., Christodoulides, C. (2020) RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro. Nature communications. 11:2797.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes