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 (2015) LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion. Cell Metabolism, 21(2), pp. 262-272.

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Abstract

Summary 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. © 2015 The Authors.

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ID Code: 94197
Item Type: Journal Article
Refereed: Yes
Keywords: beta catenin, insulin, low density lipoprotein receptor related protein 5, abdominal obesity, adipocyte, adipogenesis, adipose derived stem cell, adult, anthropometry, Article, body fat, body fat distribution, bone mass, cell differentiation, cell immortalization, cell proliferation, controlled study, ex vivo study, female, gain of function mutation, gene expression, human, human experiment, human tissue, intraabdominal fat, lipid storage, male, normal human, priority journal, protein function, regulatory mechanism, Wnt signaling pathway
DOI: 10.1016/j.cmet.2015.01.009
ISSN: 1550-4131
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2015 The Authors
Deposited On: 29 Mar 2016 01:46
Last Modified: 29 Mar 2016 21:59

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