Abstract
The specific genes regulating the quantitative variation in macronutrient preference and food intake are virtually unknown. We fine mapped a previously identified mouse chromosome 17 region harboring quantitative trait loci (QTL) with large effects on preferential macronutrient intake-carbohydrate (Mnic1), total kilcalories (Kcal2), and total food volume (Tfv1) using interval-specific strains. These loci were isolated in the [C57BL/6J.CAST/EiJ-17.1-(D17Mit19-D17Mit50); B6.CAST-17.1] strain, possessing a ∼40.1 Mb region of CAST DNA on the B6 genome. In a macronutrient selection paradigm, the B6.CAST-17.1 subcongenic mice eat 30% more calories from the carbohydrate-rich diet, ∼10% more total calories, and ∼9% more total food volume per body weight. In the current study, a cross between carbohydrate-preferring B6.CAST-17.1 and fat-preferring, inbred B6 mice was used to generate a subcongenic-derived F2 mapping population; genotypes were determined using a high-density, custom SNP panel. Genetic linkage analysis substantially reduced the 95% confidence interval for Mnic1 (encompassing Kcal2 and Tfv1) from 40.1 to 29.5 Mb and more precisely established its boundaries. Notably, no genetic linkage for self-selected fat intake was detected, underscoring the carbohydrate-specific effect of this locus. A second key finding was the separation of two energy balance QTLs: Mnic1/Kcal2/Tfv1 for food intake and a newly discovered locus regulating short term body weight gain. The Mnic1/Kcal2/Tfv1 QTL was further de-limited to 19.0 Mb, based on the absence of nutrient intake phenotypes in subcongenic HQ17IIa mice. Analyses of available sequence data and gene ontologies, along with comprehensive expression profiling in the hypothalamus of non-recombinant, cast/cast and b6/b6 F2 controls, focused our attention on candidates within the QTL interval. Zfp811, Zfp870, and Btnl6 showed differential expression and also contain stop codons, but have no known biology related to food intake regulation. The genes Decr2, Ppard and Agapt1 are more appealing candidates because of their involvement in lipid metabolism and down-regulation in carbohydrate-preferring animals.
Highlights
Genes influencing the quantitative variation in caloric and macronutrient-specific intakes, which can predispose individuals to obesity and obesity-related diseases, are virtually unknown [1,2]
Macronutrient and total calorie intakes, body weight, and body composition were measured in non-recombinant subcongenicderived F2 mice
We have clearly confirmed and refined the locations of quantitative trait loci (QTL) regulating self-selected macronutrient intakecarbohydrate (Mnic1), as well as the consumption of total kilocalories (Kcal2) and total food volume (Tfv1). These food intake QTL were originally identified through genome-wide mapping [8,23] and have been reproduced in a subcongenic-derived F2 mapping population
Summary
Genes influencing the quantitative variation in caloric and macronutrient-specific intakes, which can predispose individuals to obesity and obesity-related diseases, are virtually unknown [1,2]. None of the quantitative trait loci (QTL) found in humans correspond to those identified in mice, with the exception of a locus for total energy on human chromosome 20q13.13 [7] that overlaps Kcal, a body weight-dependent QTL for kilocalorie intake on MMU2 [8]. Mice are excellent models for genetic mapping because interval-specific strains can be bred to isolate and test loci associated with specific traits. Another key advantage of using laboratory animals for studies of eating behavior instead of humans [9] is the ability to provide a controlled environment, including manipulation of the diet and accurate measurement of food consumption
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
