We propose to use the mouse model to identify genes that contribute to the interrelated phenotypes of obesity and insulin, resistance have been described in mice. However, most obesity in humans and mice is multi- factorial and results from a rich interaction of genes, most of which are unidentified. Using quantitative trial locus (QTL) mapping we have identified a number of loci for multi-genic obesity in mice. Among these loci, three show strong correlations with measures of adiposity and also coincident QTL peaks for plasma HDL cholesterol and hepatic lipase (HL) activity. This is particularly interesting first, because HL has been implicated in the relationship between HDL cholesterol and abdominal obesity in man and secondly, because obesity and HDL cholesterol are integral parts of the insulin resistance associated metabolic syndrome. Furthermore, these loci and the syntenic gene regions in humans encompass a number of candidate genes for obesity in both species. That multiple obesity related phenotypes are affected suggests that the underlying genes play critical roles in the metabolic pathways important to the complex disease. The proposed experiments will take a multi-pronged approach to identifying and characterizing these genes. First the three obesity loci will be isolated as congenics on a common genetic background allowing us to measure the metabolic effect of each locus in the absence of the variability introduced by multiple genes at other loci. Secondly, we will finely divide each locus by creating subcongenic mouse strains to more accurately map the responsible gene and to resolve possible effects from multiple closely linked genes. A major focus of this project will be to characterize each locus not only in terms of its impact on a panel of obesity related traits but also in terms of the underlying shifts in lipid metabolism. This metabolic characterization, carried out using stable isotopes to simultaneously monitor synthesis and clearance in a variety of lipid pools, not only provides better understanding of the relevant metabolism, but potentially allows us to subdivide the multiple pathways that lead to the phenotype and detect subphenotypic metabolic shifts. Metabolic and phenotypic characterization of the congenic mice will be used to localized the multigenic obesity loci to a small genetic interval (approximately 1 cM), t test the importance of a variety of candidate genes or novel new loci and, ultimately to identify the responsible genetic alterations. The detailed characterization of several genes contributing to multigenic obesity and insulin resistance will be an important step in understanding this disease.
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