| With over 61% of the U.S. population and 1.1 million global population being overweight, understanding the complex pathway of body weight development and the genes involved is still in its infancy. The BSB mouse model, developed by backcrossing C57BL/6J and SPRET/Ei F1 progenies to C57BL/6J, offers a unique advantage into understanding common human obesity. Previous BSB data demonstrated that plasma hepatic lipase (HL) protein activity is linked to a locus on mouse chromosome 7 that also influences body fat and plasma cholesterol. The hepatic lipase gene (Lipc), although well known for its role in lipoprotein metabolism, was never directly shown to be involved in the obesity pathway. To test the role of Lipc in the development of obesity and the control of plasma cholesterol levels, Lipc knockout BSB crosses were developed. This dissertation not only examines the effect of Lipc gene, but it addresses findings of novel QTL regions and obesity candidate genes among disrupted Lipc BSB crosses. In chapter 2, Lipc is identified as a candidate obesity gene. Results from Lipc knockout BSB mice demonstrate that Lipc alleles of C57BL/6J and SPRET/Ei mouse strains differ in amino acid sequence and mRNA levels, and have significantly varying effects on obesity, consistent with the hypothesis that Lipc directly influences fat mass. Furthermore, this chapter describes a novel QTL region that affects food intake. Characterization of another novel candidate obesity gene, lipin 3 (Lpin3), in Lipc knockout BSB animal model, is presented in chapter 3. We report differential expression in adipose of lean and obese mice, highly significant linkage to obesity, and non-conservative amino acid polymorphisms between Lpin3 alleles of C57BL/6J and SPRET/Ei mice. Additionally, Lpin3 is positioned under a novel BSB obesity QTL region on chromosome 2. In chapter 4, results from microarray expression profiling of lean and obese Lipc knockout BSB mice identify differentially expressed candidate obesity genes. Some of the genes identified were positioned within mouse obesity QTL regions, making them positional candidates. Although no single animal model perfectly mimics human obesity, the BSB model affords further opportunities to investigate the genetic aspects of this epidemic disease. |
