We have developed a unique experimental system to identify the genetic determinants of macronutrient selection and energy intake, eating behaviors fundamental to the development of obesity phenotypes. Previously we identified the first genetic loci in mouse controlling complex traits (quantitative trait loci or QTL) for fat, carbohydrate, and total calorie intake in mapping population C57BL/6J (B6) x CAST/Ei (CAST) mouse inbred strains, selected for their preferential consumption of fat or carbohydrate, respectively. Next we developed congenic strains to obtain independent evidence for linkage, to determine the locus more precisely, and to aid in identification of the underlying gene(s). Subsequently, a congenic strain possessing a CAST donor segment on the B6 genetic background has confirmed a Chr 17 QTL that specified two of the original, linked traits: Mnic1 (macronutrient intake-carbohydrate) and Kcal2 (kilocalorie intake). Specifically, this congenic strain eats significantly more carbohydrate and total calories per body weight, yet a similar amount of fat, compared with littermate B6 controls. Importantly, this congenic interval also confers a phenotype of increased physical activity. We hypothesize that the QTL on Chromosome 17 is either encoded by (a) a single gene locus that determines both food intake and spontaneous physical activity, or by (b) two or more genes, each determining a sub-phenotype of energy balance. A further hypothesis is that the causal gene(s) for the behavioral traits is located in a QTL within the Chr 17 congenic segment that co-localizes with transcriptionally regulated genes (cis eQTLs). Therefore in the current application, we propose: 1) To resolve the genetic regions responsible for nutrient intake and physical activity phenotypes in the Chr 17 QTL, through fine structure genetic mapping of known QTLs for nutrient intake in a congenic by recipient F2 cross, 2) To determine which genes within the fine mapped QTL exhibit expression patterns that segregate with the behavioral phenotype(s) (i.e., eQTL), by combining the congenic F2 genotypes with custom low density gene arrays, and 3) To characterize gene candidates selected from the fine mapped QTL region(s) based on their location and transcriptional regulation (eQTLs) by determining their sequence, expression and function. The long-term goal of the proposed studies is to identify the molecular mechanisms regulating food intake and activity-induced thermogenesis in the control of energy balance. Public Health Relevance: This research project has identified genetic links to dietary preferences for fat and carbohydrate, and to total calorie intake. We have developed a new animal model to study the relationship between the genetic factors responsible for physical activity and those controlling food intake. Discovering genes that are involved in these traits is of major importance toward understanding the mechanisms underlying eating behaviors that lead to obesity, and the control of energy balance.
