Regulation of adipocyte differentiation and metabolism

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DESCRIPTION (provided by applicant): In the past funding period, we have performed novel studies demonstrating an important role for Wnt signaling as an inhibitor of adipogenesis in cultured preadipocytes and in transgenic mice. Our studies have demonstrated that Wnt10b is expressed in preadipocytes and stromal vascular cells and decreases rapidly upon induction of adipogenesis. Further, we found that Wnt10b regulates adipogenesis through suppression of C/EBPalpha and PPARgamma and that inhibition of endogenous Wnt10b with neutralizing antisera stimulates adipogenesis of cultured preadipocytes. Transgenic mice expressing Wnt10b in adipose tissue have reduced adipose tissue. FABP4-Wnt10b mice consuming a high fat diet are resistant to diet-induced and genetic-obesity, and these mice are more glucose-tolerant and insulin-sensitive than controls. Our studies have also expanded the role for Wnt10b from simple inhibition of preadipocyte differentiation to modulating fate of multipotent stem cells. Thus, FABP4-Wnt10b mice have a four-fold increase in trabecular bone. This appears to be a direct effect of Wnt10b to stimulate osteoblastogenesis and decrease adipogenesis of resident mesenchymal progenitor cells in marrow. Further support for a critical role for Wnt10b in governing fate of mesenchymal precursors comes from our observations that Wnt10b -/- mice have approximately 30% less trabecular bone and a corresponding decrease in serum osteoblast markers. Although we have made considerable progress in our studies on the effects of Wnt signaling on adipogenesis, how autocrine and paracrine signals in cultured cells and adipose tissue regulate endogenous Wnt signaling remains unknown. In this competitive renewal of DK51563, we propose experiments to test the hypotheses that Wnt activity in precursor cells is comprised of competing contributions from multiple Wnts and secreted frizzled-related proteins (sFRP) in preadipocytes and adipocytes, and that Wnt signaling inhibits adipogenesis by repressing the expression and/or activity of PPARgamma. Thus, the specific aims of this grant application are to: Specific Aim 1: Investigate activity and regulation of Wnt signaling molecules including Wnts, Fzd, and sFRPs. Specific Aim 2: Investigate mechanisms whereby Wnt signaling inhibits expression of PPARgamma. Successful completion of these specific aims will provide important insight into fat cell differentiation and metabolism, and provide insight into the medical problems of obesity and type II diabetes, two major health risks in the United States.