Polygenic regulation of murine obesity

Lsu Pennington Biomedical Research Ctr, Baton Rouge LA

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Abstract

DESCRIPTION (provided by applicant): The identification of a novel polygenic obesity gene is the primary goal of this research. Obesity is a disease of excess adipose tissue and the second most preventable cause of death in the United States today. In 2000, an estimated $117 billion was spent treating obesity, primarily on type 2 diabetes, coronary heart disease and hypertension. The 2001 surgeons general report on obesity states that in 1999, 61% of Americans are overweight, along with 13% of children and adolescents. Obesity has doubled since 1980, while overweight among adolescents has tripled. Only 3% of all Americans meet at least four of the five federal recommendations for the intake of grains, fruits, vegetables, diary products, and meats. Less than 33% of Americans exercise for the federally recommended duration and frequency, while 40% of adults are sedentary. Thus, regulation of adiposity through diet and activity, as a public health directive, is inadequate to control this epidemic. Most human obesity is polygenic and genetic variation underlies complex diseases like obesity. We are developing new murine models for polygenic obesity to understand the genetic basis for this disease and to identify the genes responsible. We describe a novel obesity gene positioned within a small 5.2-6.5 cM of mouse Chromosome 2 that regulates adiposity in response to a high fat diet. A congenic mouse strain carrying this gene is significantly reduced in adiposity when fed a high fat diet - most likely due to increased energy expenditure rather than altered food intake- when compared to the background dietary obesity susceptible strain. This observation will be confirmed and extended in subcongenic mouse strains generated to fine-map the location of this gene to an even smaller 0.2-0.5 cM genetic region. Using mouse and human genomic sequence resources, and custom cDNA microarray analysis, we will identify all polymorphic genes in this smaller region that encode variation in protein sequences between the donor and background strains or that differ in expression levels in response to genotype and/or diet composition. The identity of these candidate genes will form the basis behind directed functional assays in downstream studies to identify the underlying novel polygenic obesity gene.