Genetic factors are important in determining the risk for development of obesity as are environmental factors such as the percentage of fat in the diet. The long range goal is to characterize the genetic basis for the predisposition to obesity when challenged with a high-fat diet. Dr. West used an intercross between two strains, one susceptible to dietary fat induced obesity and one resistant, and identified six loci which have a significant effect on the susceptibility to dietary fat. The original Aims were to 1) complete a linkage map of the loci controlling differential sensitivity to dietary obesity in the AKR/J x SWR/J mouse model; 2) to evaluate the role of specific genetic loci linked to dietary obesity in the AKR/J x SWR/J model in several other genetic models of dietary obesity; 3) to develop congenic strains for four of the locus; and 4) to evaluate the role of specific candidate genes at these loci. The applicant has made excellent progress, completing the genotyping on the primary cross with the identification of 6-7 loci, constructing a number of congenics to the N5 generation, and testing several candidate genes. The current proposal is identify the gene underlying two of the loci. The first Specific Aim is to use the strategy of fine mapping and the characterization of expressed sequences in a small chromosomal region in order to identify the gene on proximal chromosome 15 of the mouse having a major effect on body fat. A candidate gene in the chromosome 12 QTL is Mod1r, a transcription factor which affects transcription of the structural gene for malic enzyme involved in carbohydrate and fat metabolism.
Specific Aim 2 will determine if AKR/J and SWR/J mice carry different alleles at the Mod1r regulatory locus and to fine map the Mod1r locus.
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