The regulation and activation of STATs in adipocytes

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DESCRIPTION (provided by applicant): Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrates. Obesity is the primary disease of fat cells and the most common metabolic disorder in the industrial world. Obesity affects >30% of the adult population in the United States and is a major risk factor for the development of non-insulin dependent diabetes mellitus (NIDDM), cardiovascular disease, and hypertension. Recent studies suggest that obesity and its related disorders may be linked to a breakdown in the regulatory mechanisms which control the expression of a variety of genes in adipocytes. Significant advances towards an understanding of these regulatory processes have been made by studying the function of transcription factors which regulate the differentiation of fat cells and are involved in the modulation of adipocyte gene expression. It is well recognized that several transcription factors are induced during adipocyte differentiation, play a critical role in the regulation of adipocyte gene expression, and are altered in conditions of obesity and/or insulin resistance. We have focused on STATs (Signal Transducers and Activators of Transcription), a family of transcription factors whose activity is largely controlled by hormone induced tyrosine phosphorylation. Our efforts have focused on two STAT proteins, STAT5A and STAT 5B, whose expression is induced during adipogenesis. Studies from our laboratory and several others have demonstrated the adipogenic capabilities of STAT 5A. Although STAT5A promotes lipid deposition in preadipocytes, there is a variety of observations to indicate that STAT 5A has anti-lipogenic actions in mature adipocytes. Growth hormone, a potent inducer of STAT 5 proteins is well known to have effects that are lipolytic, anti-lipogenic and diabetogenic. It is known that STATs can have cell specific functions, and we hypothesize that STAT5 proteins play a vital role in the regulation of genes involved in lipid metabolism and insulin resistance in adipocytes. Our preliminary studies demonstrate that STAT5 tyrosine phosphorylation in white adipose tissue is altered in rodent models of obesity. In addition, we have evidence to suggest that STAT 5 proteins may affect the endocrine properties of adipocytes by regulating the expression of several adipokines. The studies outlined in the specific aims focus on understanding the function of STAT 5 proteins in mature adipocytes and how these transcription factors affect lipogenesis, insulin sensitivity, and the production of endocrine factors from fat cells. PUBLIC HEALTH RELEVANCE: Significant advances towards understanding obesity and diabetes have been made by studying the function of transcription factors which are involved in controlling adipocyte gene expression. Our studies focus on understanding the function of STAT 5 proteins in fat cells and how these transcription factors affect lipogenesis, insulin sensitivity, and the production of endocrine factors in adipocytes.