QTL Analysis of Dietary Obesity in C57BL/6byj X 129P3/J F2 Mice: Diet- and Sex-Dependent Effects

Abstract

Obesity is a heritable trait caused by complex interactions between genes and environment, including diet. Gene-by-diet interactions are difficult to study in humans because the human diet is hard to control. Here, we used mice to study dietary obesity genes, by four methods. First, we bred 213 F2 mice from strains that are susceptible [C57BL/6ByJ (B6)] or resistant [129P3/J (129)] to dietary obesity. Percent body fat was assessed after mice ate low-energy diet and again after the same mice ate high-energy diet for 8 weeks. Linkage analyses identified QTLs associated with dietary obesity. Three methods were used to filter candidate genes within the QTL regions: (a) association mapping was conducted using >40 strains; (b) differential gene expression and (c) comparison of genomic DNA sequence, using two strains closely related to the progenitor strains from Experiment 1. The QTL effects depended on whether the mice were male or female or which diet they were recently fed. After feeding a low-energy diet, percent body fat was linked to chr 7 (LOD = 3.42). After feeding a high-energy diet, percent body fat was linked to chr 9 (Obq5; LOD = 3.88), chr 12 (Obq34; LOD = 3.88), and chr 17 (LOD = 4.56). The Chr 7 and 12 QTLs were sex dependent and all QTL were diet-dependent. The combination of filtering methods highlighted seven candidate genes within the QTL locus boundaries: Crx, Dmpk, Ahr, Mrpl28, Glo1, Tubb5, and Mut. However, these filtering methods have limitations so gene identification will require alternative strategies, such as the construction of congenics with very small donor regions.

Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

“…B6 and 129 mice differ in their susceptibility to obesity, and several quantitative trait loci (QTLs) for this phenotype have been mapped (Lin et al, 2013). One effort used computational tools to narrow QTL intervals (Su et al, 2008), and within these we find 5 cases of strain-selective WAT gene expression attributable to PPARγ binding (Figure S5A).…”

C57BL/6J mice as a polygenic developmental model of diet-induced obesity

“…, ; Lin et al. ). At least, 10 chromosomes (2, 4, 5, 7, 8, 9, 11, 12, 16, and 17) have loci implicated in the regulation of body weight, body fat, obesity, and the development of local fat depots (Reed et al.…”

“…, ; Lin et al. ). Of these, loci on chromosomes 2, 4, 9, and 16 determine body weight, body length, and adiposity (Reed et al.…”

Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice

“…C57BL/6 (B6) mice are obesity susceptible, while various 129 strains are resistant, and mouse crosses have identified risk loci but not causative genes or variants (9)(10)(11). Even within the most commonly used B6 mice, there are white adipose depot-selective responses to HFD (12).…”