Obesity is a major health problem in the United States, imparting significant metabolic and cardiovascular risk. The prevalence of obesity is predicted to continue to increase over the next several decades, and there is an urgent need to better understand adipocyte and adipose tissue physiology. Recently, my laboratory has accumulated provocative preliminary information regarding an important role for apoprotein E in adipocyte differentiated function. Our proposal is based on these preliminary data, and takes advantage of our substantial experience in the study of macrophage apoE. The goals of the current application are encompassed in three Specific Aims.
In Specific Aim # 1, we propose to analyze the molecular mechanism for the regulation of apoE gene expression by PPARgamma agonists and TNFalpha that we have already demonstrated. We will also evaluate post-translational regulation of adipocyte apoE expression.
In Specific Aim # 2, we will further expand on our preliminary data that shows expression of apoE has a significant impact on adipocyte lipid metabolism. For these studies, apoE expression will be manipulated by stable transfection, adenoviruses or interfering RNA's. We will also evaluate adipocytes isolated from apoE knockout mice and control mice. We also plan to extend our observations to an in vivo model by transplanting adipose tissue from apoE knockout mice to wild-type mice in order to evaluate parameters of gene expression and lipid metabolism in transplanted tissue.
In Specific Aim # 3, we will investigate potential heterogeneity for regulation of apoE expression, or for the effect of apoE expression on adipocyte lipid metabolism, based on the source of adipose tissue. For these studies, adipose tissue will be collected from the gluteal and abdominal subcutaneous regions, and from the intraperitoneal visceral region, of patients undergoing bariatric surgery; and utilized for isolation of adipocytes. ? ? ?
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