The prevalence of obesity is burgeoning in the United States. As a result, obesity-related metabolic disordersthat confer increased CVD risk, including diabetes, dyslipidemia, and hypertension are reaching epidemicproportions. Susceptibility to the adverse metabolic consequences of obesity varies widely in the population:modest increases in adiposity lead to severe metabolic decompensation in some individuals, whereas othersmaintain a normal metabolic profile despite severe obesity. The overall goal of this project is to identifyspecific genetic mechanisms that account for the variability of metabolic responses to excess body weightand to evaluate the therapeutic potential of agents that target these mechanisms. The study includes threecomplementary strategies: First, we will sequence selected candidate genes in a large, multi-ethnicpopulation (The Dallas Heart Study) in which each participant has undergone extensive metaboliccharacterization and relate the phenotypes to selected genotypes. Our focus will be on two groups of genes:1) genes encoding circulating proteins that carry metabolic signals between the brain, liver, adipose tissue,and intestine ('metabokines'), and 2) genes encoding selected transcriptional regulatory molecules thanrespond to metabolic signals ('cellular metabolic regulators'). Included in these studies are genes beingmechanistically interrogated in Projects 1-3. Second, we will use genome-wide methods as unbiasedapproaches toward the discovery of new genes and sequence variants that contribute to inter-individualdifferences in the metabolic responses to obesity. Third, we will collaborate with investigators in Projects 4& 5 and perform detailed studies of glucose and lipid metabolism in both mice and humans to elucidate themechanistic basis for genetic variation in susceptibility to the adverse metabolic consequences of obesity.This ambitious, interdisciplinary program leverages our established strengths in pairing careful phenotypiccharacterization with comprehensive genetic analyses in humans to discover new genes and sequencevariations contributing to metabolic traits. In addition we have established collaborations that provide accessto large, prospective population studies in which the effects of genetic sequence variants can be rigorouslyvalidated. These collaborations, together with the complementary expertise of our collaborators in Projects1-5 greatly expand the scientific scope of our studies and increases our potential to identify new therapeutictargets and approaches to prevent and treat the adverse metabolic consequences of obesity.
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