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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.

Original publication

DOI

10.1016/j.cmet.2015.01.009

Type

Journal article

Journal

Cell Metab

Publication Date

03/02/2015

Volume

21

Pages

262 - 272

Keywords

Adipogenesis, Adipose Tissue, Adult, Alleles, Body Fat Distribution, Dose-Response Relationship, Drug, Female, Healthy Volunteers, Humans, Low Density Lipoprotein Receptor-Related Protein-5, Male, Middle Aged, Mutation, Stem Cells, Thiazolidinediones, Transcriptional Activation, beta Catenin