EXCEED THE SPACE PROVIDED. The long term goal of my research program is to determine the molecular mechanisms by which extracellular signals regulate adipocyte differentiationand metabolism.We have pioneered investigations into the role of Wnt signalingas a potent, endogenously produced inhibitorof adipogenesis. Wntl0b acts as an adipogenic switch, which must be shut off for cultured preadipocyte models to differentiate in vitro. Based on the role of Wntl0b in white adipogenesis in cell culture, we hypothesize that Wntl0b also regulates development of white adipose tissue (WAT) and brown adipose tissue (BAT) in the integrativesetting of the organism. To test this hypothesis, we have created transgenic mice inwhich Wntl0b is expressed under control of the adipocyte-specific promoter, 422/aP2. Our preliminarydata indicate that Wntl0b transgenic mice are almost devoid of WAT. In addition to itseffects on development of WAT, our data suggest that Wntl0b also inhibits development of brown adipocytes within mice and withincultured cell models. Because littleis known about the regulation of BAT development, our studies will beseminal to our understanding of this important metabolic and thermogenic tissue. The role of Wntl 0b in development of adipose tissues will also be explored in Wntl 0b -/- mice. Thus, the Specific Aims ofthis proposal are to: 1) Investigate the role of Wntl0b in development of WAT. Expedments include molecular and mechanistic analyses of how Wntl0b regulates adipocyte differentiationand metabolism, 1) Investigate the role of Wntl0b in development of BAT. Experiments include molecular and mechanistic analyses of how Wnt 10b regulates BAT development in vivo and brown adipogenesis in cultured ceils. 1) Determine effects of Wntl0b on energy balance. Variables measured will include food intake, weight gain, body composition, metabolic rate, respiratoryquotient, locomotoractivity, and body temperature. Effects on energy balance will be determined as control and Wnt transgenic or null mice adapt to fasting, cold stress, genetic or diet-induced obesity. Understanding the role of Wnt signalingin the developmentof WAT and BAT will provide important insight into the medical problems of obesity and type II diabetes, two major health risks in the United States. The identificationof Wntl0b as a susceptibility gene for dysregulated development of WAT in mice will provide proof of principle that Wntl0b is important for normal and pathologicaldevelopment of adipose tissue in the human population. PERFORMANCE SITE ========================================Section End===========================================
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