Genetic resistance to diet-induced obesity in chromosome substitution strains of mice

Abstract

Discovery of genes that confer resistance to diseases such as diet-induced obesity could have tremendous therapeutic impact. We previously demonstrated that the C57BL/6J-Chr(A/J)/NaJ panel of chromosome substitution strains (CSSs) is a unique model for studying resistance to diet-induced obesity. In the present study, three replicate CSS surveys showed remarkable consistency, with 13 A/J-derived chromosomes reproducibly conferring resistance to high-fat-diet-induced obesity. Twenty CSS intercrosses, one derived from each of the 19 autosomes and chromosome X, were used to determine the number and location of quantitative trait loci (QTLs) on individual chromosomes and localized six QTLs. However, analyses of mean body weight in intercross progeny versus C57BL/6J provided strong evidence that many QTLs discovered in the CSS surveys eluded detection in these CSS intercrosses. Studies of the temporal effects of these QTLs suggest that obesity resistance was dynamic, with QTLs acting at different ages or after different durations of diet exposure. Thus, these studies provide insight into the genetic architecture of complex traits such as resistance to diet-induced obesity in the C57BL/6J-Chr(A/J)/NaJ CSSs. Because some of the QTLs detected in the CSS intercrosses were not detected using a traditional C57BL/6J x A/J intercross, our results demonstrate that surveys of CSSs and congenic strains derived from them are useful complementary tools for analyzing complex traits.

Fig. 1

Time course, traits, and metrics for body weight studies. IW = initial weight, MW = midpoint weight, FW = final weight, BMI = body mass index, EWG = mean weight gain per day during the first half of the study, FWG = mean weight gain per day during the second half of the study, WG = mean weight gain per day during the entire study, IA = initial age (days), MA = midpoint age (days), FA = final age (days). This study design was used for all studies except R-ARC (see Methods)

Fig. 2

Genetic and diet effects on patterns of weight gain. Male mice (n = 24–30 per strain) were raised on one of four diets and weighed at 2-week intervals. The mean body weight for each strain-diet combination at each time point is plotted. Diet abbreviations: HFSC = high-fat, simple carbohydrate; HFCC = high-fat, complex carbohydrate; LFSC = low-fat, simple carbohydrate; LFCC = low-fat, complex carbohydrate

Fig. 3

Mean-difference plots for replicate CSS surveys. The difference between the mean trait values (IW, FW, BMI) for each CSS in R-WOL and R-ARC was calculated and plotted versus the mean trait value for each CSS in R-WOL and R-ARC. The mean difference among all CSSs and the 95% confidence intervals (±2 standard deviations) for the mean difference were calculated and plotted. Parental strains and CSSs that are outside the 95% confidence intervals are identified

Fig. 4

Genome surveys of intercross progeny derived from the 20 CSS intercrosses. The LOD scores for each cross are plotted. 0.05 (—) and 0.63 (…) thresholds are indicated. These thresholds were calculated after correction for testing 7 traits and 20 crosses

Fig. 5

FW for CSS intercross progeny versus B6. The CSS from which each intercross population was derived is indicated (x axis), the mean FW from each intercross is indicated by a horizontal line, and * along the x axis indicates that the FW for the intercross was significantly different from B6 (p < 0.05) after multiple-testing correction (Supplementary Table 6). Individuals are marked with a filled circle if a significant or suggestive QTL was detected in the intercross analysis, and with a open circle if a QTL was not detected. X indicates B6. Obesity-resistant and obesity-susceptible strains were categorized according to results of the replicate HFSC surveys (consistently resistant strains) and are highlighted in blue and red, respectively

Fig. 6

Summary of diet-induced obesity in CSSs. The results of the CSS surveys, the CSS intercrosses (FW QTLs), and the comparisons of the mean FW for intercross progeny versus B6 are presented for each chromosome (listed at the top of each column). Studies were conducted on the high-fat, simple carbohydrate (HFSC) diet, unless otherwise indicated (low-fat, complex carbohydrate, LFCC). A gray box indicates that a QTL for FW was detected. For the CSS intercrosses, both significant and suggestive QTLs detected are presented. NR = not relevant