Fellowhip for Kalyani Bharadwaj: Angiotensin/PPAR interactiosn in the regulation of Adipose Tissue Mass in Diet-Induced

Approximately, 300,000 US adult deaths per year has been attributed to obesity. Obesity is a multifactorial pathology associated with several cardiovascular complications including hypertension. Adipose tissue is known to contain all the components of the renin-angiotensin system; however, functions of angiotensin II (Angll) at adipocytes are not well understood. Previous studies in the sponsor's laboratory demonstrate that chronic infusion of Angll to rats reduces adipose tissue mass. Peroxisome Proliferator Activated Receptor gamma (PPARgamma) is a transcription factor involved in adipogenesis and diet-induced adipocyte hypertrophy. Preliminary studies by the applicant demonstrate that PPARgamma mRNA expression is decreased in rats infused with Angll. In a model of diet-induced obesity with elevated pressure, the ability of Angll to downregulate PPARgamma was diminished. In this model of obesity-related hypertension, results from the sponsor's laboratory demonstrate that circulating and adipose-derived levels of Angll are markedly increased. The working hypothesis of these studies is that Angll negatively regulates PPARgamma gene expression in adipose tissue, resulting in a decrease in adipocyte cell number and size. In addition, we hypothesize that in rats made obese from a high fat diet, the ability of Angll to downregulate PPARgamma in the adipose tissue is diminished, ultimately contributing to obesity-related hypertension. The first hypothesis will determine the effect of chronic infusion of Angll to normal rats on PPARgamma gene expression in adipose tissue and its influence on adipocyte number and size. In addition, we will investigate the direct effect of both local and exogenous Angll on PPARgamma expression in primary isolates of adipocytes. The purpose of these studies is to determine if PPARgamma will be differently regulated by Angll in different sized adipocytes. The second hypothesis is that rats with diet-induced obesity and hypertension are resistant to Angll downregulation of PPARgamma in adipose tissue due to sustained elevations in local and systemic Angll. Angll regulation of PPARgamma in different sized adipocytes will be examined in rats with obesity-induced hypertension from a high fat diet. Results from these studies may identify a novel mechanism linking Angll to obesity and obesity-related hypertension.