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LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion
Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the ro...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321886/ https://www.ncbi.nlm.nih.gov/pubmed/25651180 http://dx.doi.org/10.1016/j.cmet.2015.01.009 |
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author | Loh, Nellie Y. Neville, Matt J. Marinou, Kyriakoula Hardcastle, Sarah A. Fielding, Barbara A. Duncan, Emma L. McCarthy, Mark I. Tobias, Jonathan H. Gregson, Celia L. Karpe, Fredrik Christodoulides, Constantinos |
author_facet | Loh, Nellie Y. Neville, Matt J. Marinou, Kyriakoula Hardcastle, Sarah A. Fielding, Barbara A. Duncan, Emma L. McCarthy, Mark I. Tobias, Jonathan H. Gregson, Celia L. Karpe, Fredrik Christodoulides, Constantinos |
author_sort | Loh, Nellie Y. |
collection | PubMed |
description | Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders. |
format | Online Article Text |
id | pubmed-4321886 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-43218862015-02-14 LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion Loh, Nellie Y. Neville, Matt J. Marinou, Kyriakoula Hardcastle, Sarah A. Fielding, Barbara A. Duncan, Emma L. McCarthy, Mark I. Tobias, Jonathan H. Gregson, Celia L. Karpe, Fredrik Christodoulides, Constantinos Cell Metab Article Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders. Cell Press 2015-02-03 /pmc/articles/PMC4321886/ /pubmed/25651180 http://dx.doi.org/10.1016/j.cmet.2015.01.009 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Loh, Nellie Y. Neville, Matt J. Marinou, Kyriakoula Hardcastle, Sarah A. Fielding, Barbara A. Duncan, Emma L. McCarthy, Mark I. Tobias, Jonathan H. Gregson, Celia L. Karpe, Fredrik Christodoulides, Constantinos LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion |
title | LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion |
title_full | LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion |
title_fullStr | LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion |
title_full_unstemmed | LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion |
title_short | LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion |
title_sort | lrp5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321886/ https://www.ncbi.nlm.nih.gov/pubmed/25651180 http://dx.doi.org/10.1016/j.cmet.2015.01.009 |
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