RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro

Nellie Y. Loh, James E. N. Minchin, Katherine E. Pinnick, Manu Verma, Marijana Todorčević, Nathan Denton, Julia El-Sayed Moustafa, John P. Kemp, Celia L. Gregson, David M. Evans, Matt J. Neville, Kerrin S. Small, Mark I. McCarthy, Anubha Mahajan, John F. Rawls, Fredrik Karpe () and Constantinos Christodoulides ()
Additional contact information
Nellie Y. Loh: University of Oxford
James E. N. Minchin: Duke University
Katherine E. Pinnick: University of Oxford
Manu Verma: University of Oxford
Marijana Todorčević: University of Oxford
Nathan Denton: University of Oxford
Julia El-Sayed Moustafa: King’s College
John P. Kemp: The University of Queensland Diamantina Institute, University of Queensland
Celia L. Gregson: University of Bristol, Southmead Hospital
David M. Evans: The University of Queensland Diamantina Institute, University of Queensland
Matt J. Neville: University of Oxford
Kerrin S. Small: King’s College
Mark I. McCarthy: University of Oxford
Anubha Mahajan: University of Oxford
John F. Rawls: Duke University
Fredrik Karpe: University of Oxford
Constantinos Christodoulides: University of Oxford

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16592-z

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