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

Author

Listed:
  • Nellie Y. Loh

    (University of Oxford)

  • James E. N. Minchin

    (Duke University
    University of Edinburgh)

  • 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
    Bristol Medical School, University of Bristol)

  • Celia L. Gregson

    (University of Bristol, Southmead Hospital)

  • David M. Evans

    (The University of Queensland Diamantina Institute, University of Queensland
    Bristol Medical School, University of Bristol)

  • Matt J. Neville

    (University of Oxford
    NIHR Oxford Biomedical Research Centre, OUH Foundation Trust)

  • Kerrin S. Small

    (King’s College)

  • Mark I. McCarthy

    (University of Oxford
    NIHR Oxford Biomedical Research Centre, OUH Foundation Trust
    University of Oxford)

  • Anubha Mahajan

    (University of Oxford
    University of Oxford)

  • John F. Rawls

    (Duke University)

  • Fredrik Karpe

    (University of Oxford
    NIHR Oxford Biomedical Research Centre, OUH Foundation Trust)

  • Constantinos Christodoulides

    (University of Oxford)

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.

Suggested Citation

  • 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. Nev, 2020. "RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16592-z
    DOI: 10.1038/s41467-020-16592-z
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    Cited by:

    1. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Saaket Agrawal & Minxian Wang & Marcus D. R. Klarqvist & Kirk Smith & Joseph Shin & Hesam Dashti & Nathaniel Diamant & Seung Hoan Choi & Sean J. Jurgens & Patrick T. Ellinor & Anthony Philippakis & Me, 2022. "Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Wenmin Zhang & Robert Sladek & Yue Li & Hamed Najafabadi & Josée Dupuis, 2024. "Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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