LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion

Abstract

SummaryCommon 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.

Dermal white adipose tissue: a new component of the thermogenic response

“…This makes it diffi cult to distinguish sWAT from dWAT. Studies of mice suggest that this distinction may be important: dWAT and sWAT are developmentally, morphologically, biochemically, and functionally distinct ( 1,(14)(15)(16)(17)(18)(19)(20). Unfortunately, in previous literature, these depots have typically been referred to using the general "subcutaneous" descriptor, and without a specifi c visual indication, it is diffi cult to deduce the subject of these reports.…”

“…Different depots secrete specifi c adipokines and systemic effectors, and have characteristic patterns of innervation and vascularization ( 45 ). For example, the molecular signaling controlled by insulin, cortisols, and adrenergic agonists is different in various depots ( 19,44,46 ). It is not yet known which aspects of the molecular regulation of WAT are shared by dWAT, and which are unique.…”

“…Thus, the heterogeneous cell fractions extracted from distinct WAT depots [stromal vascular fractions (SVFs)], when compared by transcriptional profi ling, show different and characteristic gene expression. Some of these differences have been implicated in the distinct properties of each WAT depot ( 18,19,44 ). For example, each depot has a characteristic capacity to store and mobilize fatty acids in response to specifi c physiological challenges.…”

Lrp5 Has a Wnt-Independent Role in Glucose Uptake and Growth for Mammary Epithelial Cells

“…However, many of these studies have focused on Wnt ligand-regulated changes in metabolism and canonical Wnt signaling outputs to explain their phenotypes. For example, in humans, rare mutations in Lrp5 control bone and cardio-metabolic disorders, such that gain-of-function mutations lead to high bone mass and enhanced lower body fat accumulation, whereas loss-of-function mutations give low bone mineral density and increased abdominal adiposity (51,52). Other investigators have shown that Lrp5 knockout mice show normal glucose levels but impaired glucose tolerance, thus showing less insulin secretion in response to glucose administration (14).…”

Emerging nonmetabolic functions of skin fat

“…Anagen hair follicles both respond to 52,75 and modulate Wnt signalling via secreted ligands and antagonists 51–53 . The direct effect of canonical Wnt signalling is largely inhibitory in non-skin WAT 76–79 , and this holds true for dermal fat 48,80 . Dramatic dWAT loss is observed in mice whose dermal cells overexpress constitutive stabilized β-catenin 80 .…”