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; Constantinos Christodoulides

doi:10.1038/s41467-020-16592-z

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, Constantinos Christodoulides

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Abstract / Description of output

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.

Original language	English
Article number	2797
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-16592-z
Publication status	Published - 3 Jun 2020

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s41467-020-16592-zFinal published version, 2.38 MBLicence: Creative Commons: Attribution (CC-BY)

BHF Research Excellence Award (2) (renewal) Grant 1
Mullins, J., Bailey, M., Beqqali, A., Caporali, A., Crisan, M., Mansley, M., Meloni, M., Reynolds, R. & Wu, J.
UK-based charities
1/04/14 → 30/06/19
Project: Research

James Minchin
- james.minchined.acuk
- Deanery of Clinical Sciences - Senior Lecturer
- Centre for Cardiovascular Science
Person: Academic: Research Active

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Loh, N. Y., Minchin, J. E. N., Pinnick, K. E., Verma, M., Todorčević, M., Denton, N., El-Sayed Moustafa, J., P. Kemp, J., 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, Article 2797. https://doi.org/10.1038/s41467-020-16592-z

@article{207370cc53a447299380430e00652d50,

title = "RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro",

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.",

author = "Loh, {Nellie Y.} and Minchin, {James E. N.} and Pinnick, {Katherine E.} and Manu Verma and Marijana Todor{\v c}evi{\'c} and Nathan Denton and {El-Sayed Moustafa}, Julia and {P. Kemp}, John and Gregson, {Celia L.} and Evans, {David M.} and Neville, {Matt J.} and Small, {Kerrin S.} and McCarthy, {Mark I.} and Anubha Mahajan and Rawls, {John F.} and Fredrik Karpe and Constantinos Christodoulides",

year = "2020",

month = jun,

day = "3",

doi = "10.1038/s41467-020-16592-z",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Loh, NY, Minchin, JEN, Pinnick, KE, Verma, M, Todorčević, M, Denton, N, El-Sayed Moustafa, J, P. Kemp, J, Gregson, CL, Evans, DM, Neville, MJ, Small, KS, McCarthy, MI, Mahajan, A, Rawls, JF, Karpe, F & Christodoulides, C 2020, 'RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro', Nature Communications, vol. 11, 2797. https://doi.org/10.1038/s41467-020-16592-z

TY - JOUR

T1 - RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro

AU - Loh, Nellie Y.

AU - Minchin, James E. N.

AU - Pinnick, Katherine E.

AU - Verma, Manu

AU - Todorčević, Marijana

AU - Denton, Nathan

AU - El-Sayed Moustafa, Julia

AU - P. Kemp, John

AU - Gregson, Celia L.

AU - Evans, David M.

AU - Neville, Matt J.

AU - Small, Kerrin S.

AU - McCarthy, Mark I.

AU - Mahajan, Anubha

AU - Rawls, John F.

AU - Karpe, Fredrik

AU - Christodoulides, Constantinos

PY - 2020/6/3

Y1 - 2020/6/3

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-020-16592-z

DO - 10.1038/s41467-020-16592-z

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 2797

ER -

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

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BHF Research Excellence Award (2) (renewal) Grant 1

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James Minchin

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