The long-term goal of my research program is to determine the molecular mechanisms by which extracellular signals regulate adipocyte differentiation and metabolism. We have pioneered investigations into the role of Wnt signaling as a potent, endogenously produced inhibitor of adipogenesis. Wnt10b acts as an adipogenic switch, which must be shut off for cultured preadipocyte models to differentiate in vitro. Based on the role of Wnt10b 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 integrative setting of the organism. To test this hypothesis, we have created transgenic mice in which Wnt10b is expressed under control of the adipocyte-specific promoter, 422/aP2. Our preliminary data indicate that Wnt10b transgenic mice are almost devoid of WAT. In addition to its effects on development of WAT, our data suggest that Wnt10b also inhibits development of brown adipocytes within mice and within cultured cell models. Because little is known about the regulation of BAT development, our studies will be seminal to our understanding of this important metabolic and thermogenic tissue. The role of Wnt10b in development of adipose tissues will also be explored in Wnt10b -/- mice. Thus, the Specific Aims of this proposal are to:1) Investigate the role of Wnt10b in development of WAT. Experiments include molecular and mechanistic analyses of how Wnt10b regulates adipocyte differentiation and metabolism,1) Investigate the role of Wnt10b in development of BAT. Experiments include molecular and mechanistic analyses of how Wnt 10b regulates BAT development in vivo and brown adipogenesis in cultured cells.1) Determine effects of Wnt10b on energy balance. Variables measured will include food intake, weight gain, body composition, metabolic rate, respiratory quotient, locomotor activity, 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 signaling in the development of 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 identification of Wnt10b as a susceptibility gene for dysregulated development of WAT in mice will provide proof of principle that Wnt10b is important for normal and pathological development of adipose tissue in the human population.
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