AN OBESITY LOCUS ON MOUSE CHROMOSOME 7

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Obesity results in significant morbidity and mortality in the North American population and effective long-term treatments are not available. The etiology of obesity is complex with both genetic predisposition and environmental factors playing a role. One approach to further our understanding of the causal factors responsible for obesity is to identify the genes and characterize the genetic mechanisms contributing to the disease. An understanding of the genetic mechanisms contributing to obesity may lead to new therapeutic developments and will help us to understand the relevant environmental factors causing obesity. Although finding genes contributing to a complex disease in human populations is possible, appropriate mouse models offer many advantages including the availability of inbred strains and rich genetic resources. It is likely that the same pathways involved in energy metabolism in mouse models will be involved in human disease. There is now significant evidence from a number of different studies in independent laboratories that a genetic locus on proximal mouse chromosome 7 is contributing to variation of body fat in the mouse. We have preliminary data using radiation deletion mutants in the mouse indicating that this gene is having a significant effect on body fat content, is paternally imprinted, and we have localized it to a narrow region just distal to the pink eyed dilution locus on mouse chromosome 7. In this application we propose to further narrow the critical region containing the gene using a panel of additional deletion mutants. We will physically map the critical region, develop a gene expression map for this area and evaluate the role of candidate genes which are located in this physical map. At the end of this project we will have identified a gene contributing to the regulation of body fat in the mouse. Follow-up studies in subsequent funding periods will be dir ected at characterizing the mechanism of action of this gene and determining if it is involved in human obesity.