Genetic mapping and phenotypic analyses of obesity genes in the mouse

Obesity is a multifactorial disease influenced by genetics, the environment, gene-gene interactions, and gene-environment interactions. The complex nature of obesity makes it particularly difficult to dissect the individual components that contribute to the disease. One effective method to isolate genes influencing obesity and related traits is the use of mouse breeding strategies to identify quantitative trait loci (QTL), or chromosomal regions influencing a quantitative trait such as body weight or fat mass, followed by the production of congenic mice to isolate and narrow the QTL. The objective of these experiments was to map obesity and obesity-related genes using congenic mice as well as evaluate the interaction of obesity genes and the environment. To map and confirm a QTL previously identified in a mouse model of obesity, I constructed a chromosome 15 congenic mouse line originally derived from the BSB cross, an interspecific backcross involving C57BU6J and the wild-derived Mus spretus. Linkage analysis of the donor region showed significant QTLs for body weight in males and females with congenic mice weighing less than their background littermates. In females, I also detected a strong QTL for femoral adipose tissue depot weight, corrected for body weight. To fine map a BSB QTL on chromosome 2, I produced overlapping subcongenics to narrow an obesity QTL previously captured in a congenic line. The QTL region was reduced from 27 Mb to 7 Mb in size and an interval specific microarray identified several candidate genes. This candidate gene list included prohormone convertase 2 which showed a decrease in expression in whole brains of congenic mice compared to their background littermates. To better understand the interactions of genetic obesity and the environment, I investigated diet and exercise intervention on the lethal yellow agouti mouse, a monogenic model of obesity. It was shown that environmental perturbations affect those mice with obesity causing mutations differently than normal mice. These studies aid in the discovery of obesity causing genes and the understanding of their response to environmental influences.