Adipose tissue plays an important role in maintaining normal physiological functions associated with lipid and glucose metabolism such that the disruption of these functions leads to increasing risks for both cardiovascular disease and type 2 diabetes. The mechanisms by which adipose tissue mediates an individual's risk of developing cardiovascular disease and diabetes are not clearly understood. However, results of recent studies have demonstrated that adipose tissue is an active endocrine organ producing a number of proteins. These proteins have potent effects on a variety of metabolic pathways and in particular appear to exert a significant effect on lipid and glucose regulation. In addition, there is growing evidence that dietary make-up, particularly the fat and cholesterol content, can have significant effects on the expression of many genes involved in metabolic processes including those associated with adipose tissue function. As part of the current study, we have now begun to identify quantitative trait loci (QTLs) with significant effects on the regulation of adipose tissue function and to assess their impact on cardiovascular disease and type 2 diabetes. We propose to examine the effects of specific positional candidate genes for significant QTLs on phenotypes related to adiposity and adipose tissue endocrine function. We will evaluate further the relevance for humans of detected candidate gene associations in the baboon by conducting replication analyses using high density SNP data from a large-scale human cardiovascular genetics study. We also propose to examine the effects of a chronic high cholesterol, high fat dietary challenge on the composition and function of adipose tissue and to determine how changes in the characteristics of adipose tissue relate to changing risk profiles for cardiovascular disease and diabetes.
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