A Role for sFRP5 in Adipocyte Biology and Obesity.

Abstract

Research conducted over the last decade has established the Wnt/β-catenin signaling pathway as an important regulator of adipocyte differentiation. It is now known that preadipocytes secrete various Wnt proteins that act through autocrine/paracrine mechanisms to inhibit preadipocyte differentiation. Further complexity arises through the regulated expression of endogenous inhibitors of Wnt/β-catenin signaling, including the family of secreted frizzled-related proteins (sFRPs). sFRPs are thought to prevent downstream Wnt signaling by binding to and sequestering Wnt molecules in the extracellular space, although recent reports have indicated sFRPs can function through mechanisms independent of Wnt inhibition. Here we have sought to characterize a novel function for sFRP5 in adipocyte biology and obesity. We show that sFRP5 expression is strongly induced during adipocyte differentiation in vitro and in various models of obesity. Furthermore, sFRP5 expression is highly correlated with increasing adiposity and adipocyte size. Mice that lack functional sFRP5 resist diet-induced obesity as evidenced by lower total body weight and decreased fat mass. Detailed morphometric analysis revealed that sFRP5Q27stop mice challenged with a high fat diet have fewer large adipocytes than wild type mice. Utilizing a model of adipose tissue transplantation, we show that sFRP5 regulates adipocyte size during obesity in a tissue autonomous manner. In our studies to elucidate the mechanism of action of sFRP5, we found that sFRP5 regulates adipocyte clustering of 3T3-L1 cells, a similar result to that observed upon activation of integrin signaling in adipocytes. Indeed, we show that sFRP5 can functionally interact with integrins in a gel contraction assay, and that activation of the integrin/ERK signaling pathway is altered in two distinct models of sFRP5-deficient adipocytes in culture. Thus we provide evidence that sFRP5 regulates adipocyte expansion during obesity, and that the integrin/ERK cascade may mediate these effects. Finally, we describe additional preliminary results suggesting that sFRP5 may directly or indirectly regulate the seemingly distinct processes governing food intake under specific conditions, bone mass, and mitochondrial oxidative phosphorylation in adipocytes, thus expanding the scope of sFRP5 function and providing insight into the overall impact of this factor in vertebrate biology.