期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-16592-z
关键词
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资金
- British Heart Foundation Clinical Research Fellowship [FS/16/45/32359]
- British Heart Foundation [PG/12/78/29862]
- Heart Research UK
- European Foundation for the Study of Diabetes
- National Institutes of Health [R01-DK093399]
- American Heart Association [11POST7360004, 13POST16930097]
- University of Edinburgh Fellowship
- Versus Arthritis [20000]
- Wellcome [090532, 203141, 106130, 098381, 212259]
- NIDDK [U01DK105535]
- MRC [M004422/1, L0201491/1, J010642/1, MR/L01999X/1, MR/M004422/1]
- Wellcome Trust [203141/Z/16/Z]
- European Community
- National Institute for Health Research (NIHR)- funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London
- University of Queensland Development Fellowship [UQFEL1718945]
- National Health and Medical Research Council (Australia) Investigator grant [GNT1177938]
- MRC [MR/L01999X/1, MR/L020149/1, MR/M004422/1, MR/J010642/1, MC_UU_12013/4, MR/S025685/1] Funding Source: UKRI
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. Genetic variants at the RSPO3 locus are associated with waist-to-hip ratio (adjusted for BMI). Here, Loh et al. describe two independent RSPO3 signals that associate with body fat distribution, perform fine-mapping and explore the function of RSPO3 in human adipocyte biology and body fat distribution in zebrafish
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