Characterization of QTL with major effects on fatness and growth on mouse chromosome 2.

Objective: To isolate and characterize a region on mouse chromosome 2 harboring quantitative trait loci with large influences on growth and fatness.

Research Methods And Procedures: A congenic line [M16i.B6-(D2Mit306-D2Mit52); MB2] was created using the polygenic obese M16i selection line as the recipient for an approximately 38-centimorgan region from C57BL/6J. Males and females from M16i and MB2 were compared for body weight, body composition, feed consumption, and additional traits at 6, 15, and 24 weeks. Interactions of genotype and environment (low and high dietary fat) were investigated. Males (8 weeks) were evaluated for fatty acid profiles in liver and for transcriptional profiles in liver and adipose.

Results: Consequences of replacing M16i alleles with C57BL/6J alleles in MB2 were maximized at 15 weeks. MB2 mice were up to 15% lighter than M16i at this age, with no differences in feed consumption. As a percentage of body weight, MB2 had dramatically less epididymal (males) or perimetrial (females) fat (1.17% vs. 2.79% pooled across sex) and lower total lipids (16.1% vs. 23.3%) than M16i. Decreased adiposity in MB2 was not dependent on gender or diet. MB2 mice also had significant decreases in levels of leptin, insulin, and glucose, decreased de novo synthesis of hepatic fatty acid, and transcriptional changes for many genes both within, and external to, the congenic region.

Discussion: Results confirm the presence and large effects of mouse chromosome 2 quantitative trait loci and further define their phenotypic consequences related to energy balance. The MB2 congenic line is a powerful resource for eventual identification of pathways and mutations within genes regulating predisposition to growth and obesity.