Increased physical activity cosegregates with higher intake of carbohydrate and total calories in a subcongenic mouse strain

Abstract

C57BL/6 J (B6) and CAST/EiJ (CAST), the inbred strain derived from M. musculus castaneus, differ in nutrient intake behaviors, including dietary fat and carbohydrate consumption in a two-diet-choice paradigm. Significant quantitative trait loci (QTLs) for carbohydrate (Mnic1) and total energy intake (Kcal2) are present between these strains on chromosome (Chr) 17. Here we report the refinement of the Chr 17 QTL in a subcongenic strain of the B6.CAST-( D17Mit19-D17Mit91 ) congenic mice described previously. This new subcongenic strain possesses CAST Chr 17 donor alleles from 4.8 to 45.4 Mb on a B6 background. Similar to CAST, the subcongenic mice exhibit increased carbohydrate and total calorie intake per body weight, while fat intake remains equivalent. Unexpectedly, this CAST genomic segment also confers two new physical activity phenotypes: 22% higher spontaneous physical activity levels and significantly increased voluntary wheel-running activity compared with the parental B6 strain. Overall, these data suggest that gene(s) involved in carbohydrate preference and increased physical activity are contained within the proximal region of Chr 17. Interval-specific microarray analysis in hypothalamus and skeletal muscle revealed differentially expressed genes within the subcongenic region, including neuropeptide W (Npw); glyoxalase I (Glo1); cytochrome P450, family 4, subfamily f, polypeptide 1 (Cyp4f15); phospholipase A2, group VII (Pla2g7); and phosphodiesterase 9a (Pde9a). This subcongenic strain offers a unique model for dissecting the contributions and possible interactions among genes controlling food intake and physical activity, key components of energy balance.

FIG. 1

Chromosome 17 and the position of the B6.CAST-17.0 (original congenic) and B6.CAST-17.1 subcongenic intervals responsible for increased carbohydrate and total energy intake, and increased physical activity. The BC-17.1 subcongenic strain carries 40.6 Mb of CAST donor DNA on proximal Chr 17 in a B6 background. The donor segment extends from D17Mit19 at 4.8Mb to D17Mit50 at 45.4Mb. The external distal marker is D17Mit107 (B6). Based on phenotypic analyses, the gene(s) responsible for the QTL lies between 4,804,477 and 45,496,289 bp on the physical map of mouse Chr 17, containing an estimated 869 genes (NCBI – Build 36.1). The gray shaded areas represent yet undefined regions of CAST- or B6-derived genomic DNA. FI, food intake; BW, body weight; SPA, spontaneous physical activity.

FIG. 2

(A) Total energy expenditure (TEE) and (C) respiratory exchange ratio (RER) obtained by indirect calorimetry for 12 h light, 12 h dark, and 24 h total periods. (B, D) Plots of percent relative cumulative frequency (PRCF) of TEE and RER values, respectively. Each PRCF curve represents the data pooled from all mice (n=15) within a genotype (~4600 data points per curve), i.e., in chow-fed B6.CAST-^{D17Mit19–D17Mit50} homozygous (HOMO) and wild-type B6 (WT) subcongenic mice.

FIG. 3

(A & B) Spontaneous physical activity (X-total counts) of B6.CAST-17.1 homozygous (HOMO) and wild-type B6 (WT) subcongenic mice. In “A”, the hourly data are presented, as recorded on three successive days following 2 d of acclimation to the activity chambers. In “B”, the data are presented as the mean of 3 d for each of three activity parameters (X-TOT, X-AMB, and Z-TOT) during the lights-on (0600–1800) or dark (1800-0600) periods. An X-total (X-TOT) count measures horizontal movement >0.5 in. and is representative of small-scale, repetitive activities such as scratching and grooming. The X-ambulatory count (X-AMB) measures actual locomotion in the horizontal plane. A Z-total (Z-TOT) count represents vertical movement, i.e., rearing. n = 15 mice per genotype. *P <0.05.

FIG. 4

(A) Average daily running distance in singly-housed B6.CAST-17.1 homozygous (HOMO) and wild-type B6 (WT) subcongenic mice during days 23–37, following habituation to the wheel housing. (B) The data from “A” are presented as the mean of 15 d of activity, during lights-on (0700) and lights off (1900) periods. (C) Average body weight measured twice per week throughout the experiment, including the habituation to wheel running. *P < 0.05. n = 6 mice per genotype.