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 and 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: 262-272. doi:10.1016/j.cmet.2015.01.009


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
Title LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion
Journal name Cell Metabolism   Check publisher's open access policy
ISSN 1932-7420
1550-4131
Publication date 2015-02-03
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.cmet.2015.01.009
Open Access Status DOI
Volume 21
Issue 2
Start page 262
End page 272
Total pages 11
Place of publication Cambridge, MA United States
Publisher Cell Press [Elsevier]
Collection year 2016
Language eng
Formatted abstract
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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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