Human obesity is a familial trait with a genetic component estimated conservatively at 30%. With the exception of several single gene mutations in mice, the genes involved in obesity are still unknown. It is unlikely that the monogenic models will fully explain the genetic factors operative in human obesity, but polygenic rodent models should prove more valuable. The high degree of synteny conservation between mouse and human genomes suggests that phenotype-linked sequences obtained from mouse and rat studies will be mappable relative to the analogous phenotype in humans and will provide for direct testing of similar genes in human pedigrees Two recent advances have now put the discovery of the basis of polygenic obesity within reach: an extensive locus map of the mouse is now available and a method has been developed which allows the mapping of discrete Mendelian factors underlying a trait, but does not require prior knowledge of the nature of these factors. Thus, by measuring the phenotypic expression of obesity and specific genomic markers in progeny from appropriate genetic crosses, the number and chromosomal location of genes associated with obesity can be identified. The long-term objective of this project is to map the discrete Mendelian factors underlying obesity in two polygenic rodent models by the application of restriction fragment length polymorphism (RFLP) maps using this novel and powerful new technique. This will be accomplished by the following specific aims: 1) the genomes of our mouse and rat models of polygenic obesity will be mapped by using previously identified markers and by developing additional markers, spaced at approximately 20 cM distances along the genome, 2) the phenotypic expression of obesity will be measured in both models by measuring body composition (% fat), components of energy balance (energy intake and expenditure), nutrient substrates (triglycerides, fatty acids, 3-hydroxybutyrate and glucose), hormones (insulin and corticosterone), central regulation (hypothalamic levels and uptake of catecholamines), sympathetic nervous system activity and sensitivity (brown adipose tissue uncoupling protein and GDP-binding and basal and stimulated oxygen consumption), and an enzyme regulating fat deposition (white adipose tissue lipoprotein lipase), and 3) using the genetic markers and phenotype data, quantitative trait loci will be mapped for the quantitative trait of interest. Co-segregation of maps for the phenotypic traits will suggest interrelationships of these traits with each other and with obesity. The hypothesis that the expression of obesity in these models is mediated through nutrient and hormonal factors acting upon the sympathetic nervous system will be tested by examining this co-segregation. Using Mus musculus (strain C57BL/6J) and Mus spretus crosses, mapping of the mouse genome is well underway with over 40 markers currently available. Backcross mice have been both phenotyped and genotyped and loci associated with carcass lipid stores and plasma glycerol non-esterified fatty acids and high density lipoprotein cholesterol have been tentatively identified.
