Obesity is a major health issue in the United States and other Western countries, increasing the risk of diabetes, cardiovascular diseases and several types of cancers. In contrast, lipoatrophy, the lack of adipose tissue, is also associated with diabetes and various metabolic abnormalities. Thus, understanding the cellular and molecular basis that regulates adipocyte differentiation is necessary to develop comprehensive therapeutic strategies for the prevention and treatment of these disorders. The canonical Wnt/?-catenin pathway has been shown to inhibit adipogenesis while maintaining a dividing preadipoctye state through overexpression studies. However, its physiological importance remains to be elucidated. We reported a novel ?-catenin-associated antagonist, termed Chibby (Cby). Cby is a nuclear protein that is conserved throughout evolution. We showed that Cby interacts with the C-terminal activation domain of ?-catenin and represses ?-catenin-mediated transcriptional activation by competing with Lef-1. We further demonstrated that loss of Cby function leads to hyperactivation of the pathway in Drosophila. To gain insights into the function of Cby during vertebrate development as well as in human disease, we have created Cby-null (Cby-/-) mice. Unexpectedly, these mice exhibit reduced adiposity. Using cultured 3T3-L1 preadipocytes, we found that Cby protein levels increase during adipogenesis. Furthermore, ectopic expression of Cby causes spontaneous differentiation, and conversely, Cby RNAi almost completely blocks adipogenesis of 3T3-L1 cells. These preliminary data strongly argue that Cby is an essential proadipogenic factor. The long-term goal of this application is to elucidate the role of Cby in adipose tissue development. We propose to analyze adipose tissues in Cby-/- mice, investigate adipogenic potential of Cby-/- mouse embryonic fibroblasts in vitro, and characterize Cby using preadipocyte and pluripotent mesenchymal stem cells. Our research offers hope that blocking Cby's activity may be an effective therapy for obesity and its associated disorders. ? ?
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