Genes Modulating Diet-Induced Diabetes in Mice

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DESCRIPTION (provided by applicant): Type 2 diabetes and obesity have become epidemics in our country and it is expected that 300 million people will develop type 2 diabetes within the next 25 years. For the vast majority of these individuals, causative genes and biochemical mechanisms leading to disease development remain unknown. Human linkage studies have been helpful for <2% of single genes causing forms of type 2 diabetes, but common cases are under multigenic control, and specific causative genes have not been identified. To accelerate the identification of genes predisposing to obesity and type 2 diabetes, mouse systems are proving useful. We make use of strains A/J and C57BL/6, which are resistant and susceptible, respectively, to diet-induced obesity and type 2 diabetes. We utilize unique and novel strains derived from A/J and C57BL/6 called chromosome substitution strains (CSSs), developed by Dr. Joseph Nadeau (Case Western Univ.). Each strain has one chromosome derived from A/J amongst the genetic background of C57BL/6. These strains allow rapid assignment of specific traits, such as body weight and plasma glucose levels, to specific chromosomes. They also facilitate the next steps of congenic mapping needed to eventually fine map and identify genes controlling obesity and diabetes in the face of high fat and sugar diets. We have three specific aims, which are to (1) Identify chromosomes harboring genes controlling obesity and diabetes, and (2) Construct congenic strains containing chromosomal intervals regulating obesity and diabetes, and (3) Develop crosses for fine structure mapping. Work toward the first aim is progressing well and we have already identified several chromosomes containing A/J alleles modulating body weight and plasma glucose levels. The second and third aims will involve breeding informative CSSs and recombinant inbred lines to C57BL/6 to capture smaller chromosomal regions of active A/J alleles. Overall, this proposal will move the field forward toward identifying genes controlling the complex disorders of obesity and type 2 diabetes.