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 vertebrate organisms. Obesity is the primary disease of fat cells and a major risk factor for the development of non-insulin dependent diabetes mellitus (NIDDM), cardiovascular disease, and hypertension. Obesity and its related disorders result in dysregulation of the mechanisms that control the expression of metabolic genes in adipocytes. Significant advances towards an understanding of these regulatory processes have been made by the identification of transcription factors that regulate the differentiation of fat cells and are involved in the induction and maintenance of adipocyte gene expression. Our research has focused on the STAT family of transcription factors. STATs comprise a family of latent transcription factors that reside in the cytoplasm of resting cells. In response to a variety of stimuli, STATs become activated and translocate to the nucleus. Unlike other adipocyte transcription factors, STATs can be rapidly activated to regulate gene expression and represent a relatively unexplored paradigm in the transcriptional regulation of fat cells. We have shown that the expression of both STAT 5 proteins (STATs 5A, and 5B) strongly correlates with lipid accumulation and PPAR? expression during adipogenesis. It is known that STATs can have cell specific functions, and we hypothesize that these transcription factors play a key role in the regulation of genes involved in lipid metabolism and possibly in regulating genes that confer insulin sensitivity to the adipocyte. Our preliminary studies clearly demonstrate that STAT 5A can promote adipogenesis in non-precursor cells. In addition, we have shown that STAT 5A interacts with glucocorticoid receptor (GR) and the association of these two transcription factors is regulated during adipogenesis. Our preliminary studies have also identified some potential STAT 5 target genes in adipocytes. The studies outlined in the specific aims focus on understanding the function of STAT 5 proteins in adipocytes. We predict that these studies will lead to insights into the molecular mechanisms regulating energy homeostasis and may contribute to understanding the defects underlying obesity and NIDDM.