The prevalence of overweight and obesity reaches ~30% in industrialized countries, and obesity together with the related metabolic disorders, insulin resistance and non insulin dependent diabetes mellitus are ever growing and major health problems. Obesity has a strong genetic component and is thought to be the result of the interaction of polygenes with the environment. Consequently, much effort has gone into trying to identify genes responsible for the common forms of human obesity, however, no gene with a major effect has been identified. In contrast, remarkable progress has been made in the identification of single gene mutations causing obesity. Particularly the characterization of the genes mutated in mouse models of obesity has greatly contributed to our understanding of the disease. The value of the mouse mutations lies in the access they provide to novel metabolic and regulatory pathways involved in the etiology of obesity and related disorders in humans. New models that will further define or identify novel obesity pathways are needed to expand our understanding of this chronic disease and its sometimes life threatening associated complications. We are in a unique position at The Jackson Laboratory to discover such new obesity/type 2 diabetes models and have the proven expertise to identify their underlying molecular bases. Our institutional Deviant Search program and two NIH funded mutagenesis centers are a rich resource for new mutations. The introduction of assisted reproductive technologies allows us to quickly and efficiently produce experimental animals for phenotypic characterization and for genetic crosses to map and clone the mutations. The completion of the mouse genome greatly accelerates mutation detection. We can now capitalize on these technical advances to bring new, well-characterized mouse obesity models to the research community. We have initially selected five new mouse obesity mutations for positional cloning. These new mutations cover a spectrum of obesity phenotypes from early to late onset, moderate or morbid, and with or without accompanying type II diabetes. At the successful conclusion of this work, we will have identified at least five new obesity and diabetes genes, provided sufficient phenotypic information to make these models useful to the obesity/diabetes research community, and formed and tested hypotheses regarding their function. ? ?
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