MOLECULAR DISSECTION OF REGIONAL ADIPOSITY

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DESCRIPTION (provided by applicant): Obesity is a growing national health concern and it is closely linked to comorbidities of cardiovascular disease and diabetes. Population-based studies have indicated a strong association between regional location of excess adipose tissue and health impact, with intra-abdominal visceral adiposity resulting in the most deleterious effects. Studies in humans and rodents indicate that each white adipose tissue (WAT) depot has unique physiological and metabolic profiles. However, the gene expression patterns underlying these phenotypic distinctions have received very limited study and no gene with expression exclusive to adipocytes from one or another particular WAT depot has been described. To address the hypothesis that each WAT depot is transcriptionally distinct, we have prepared and differentially screened a murine WAT depot subtracted library and conducted pilot filter DNA array hybridization studies. Using the mouse as a model system, studies in this R21 proposal further delineate the gene expression differences between adipocytes found in each of four distinct WAT depots - omental, subcutaneous, epididymal and retroperitoneal from wild type and obese sources. These transcriptional profiles will yield critical insights into how differences in gene expression of adipocytes in various WAT depots lead to pathophysiology of regional adiposity. Two specific aims will be conducted: 1.) Utilizing DNA microarray, subtracted cloning, and differential display, we will characterize profiles of white adipocyte depot-specific gene expression. 2.) In vitro cell culture models for the high throughput study of WAT depot specific gene expression will be generated and validated. The long-term goal of this research is to identify DNA elements and their cognate transcription factors that function in WAT depot specification and gene expression in vivo. This knowledge will be used to define the molecular mechanisms that result in pathophysiology and co-morbidities of regional obesity and to design WAT depot-specific promoter constructs to conduct targeted ablation studies. Only in this way can the contribution of a particular WAT depot to health and disease be assessed and modulated in vivo; such experiments are not feasible with current molecular tools. The completion of the research plan in this R21 proposal will be a critical step in achieving these long-term goals.