Genetic Architecture of Insulin Resistance in the Mouse

Abstract

SUMMARY Insulin Resistance (IR) is a complex trait with multiple genetic and environmental components. Confounded by large differences between the sexes, environment and disease pathology, the genetic basis of IR has been difficult to dissect. Here we examine IR and related traits in a diverse population of more than 100 unique male and female inbred mouse strains after feeding a diet rich in fat and refined carbohydrates. Our results show dramatic variation in IR among strains of mice and widespread differences between sexes that is dependent on genotype. We uncover more than 15 genome-wide significant loci and validate a gene, Agpat5, associated with IR. We also integrate plasma metabolite levels and global gene expression from liver and adipose tissue to identify metabolite Quantitative Trait Loci (mQTL) and expression QTL (eQTL), respectively. Our results provide a resource for analysis of interactions between diet, sex and genetic background in IR.

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

“…In addition to prioritizing candidate genes, studies of natural variation in gene expression in mice should be useful in elucidating mechanisms relating to the gene-by-gene, gene-by-environment, and gene-by-sex interactions. 51,52,89 For example, although it is clear that genetic background contributes to weight gain and related traits in response to dietary challenge, 90 the inability to accurately ascertain environmental factors over a lifetime in humans has made molecular dissection difficult. In contrast, studies of natural variation in mice have revealed that gene-by-environment interactions can contribute substantially to the overall variance in traits such as obesity and that the underlying genes and pathways can be identified.…”

“…In contrast, studies of natural variation in mice have revealed that gene-by-environment interactions can contribute substantially to the overall variance in traits such as obesity and that the underlying genes and pathways can be identified. 51,52 Whereas numerous studies have successfully mapped cis associations, few studies have reported trans-eQTLs because of small effect sizes, multiple testing thresholds, and computational burden. 22,37,91 These issues are consistent with the low reciprocal replication rates of trans-eQTLs identified in MuTHER and METSIM cohorts.…”

“…51,52 In brief, mice from 120 strains were obtained from The Jackson Laboratory and were bred at the University of California, Los Angeles. Mice were maintained on a chow diet (Ralston Purina Company) until 8 weeks of age, when they were either continued on a chow diet (n ¼ 185 mice) or given a high-fat, high-sucrose diet (Research Diets-D12266B) for an additional 8 weeks (n ¼ 227 mice).…”

“…Plasma lipids, insulin, glucose, and HOMA-IR were determined as previously described. 52,53 The animal protocol for the study was approved by the Institutional Care and Use Committee (IACUC) at the University of California, Los Angeles. Total RNA from flash-frozen epididymal adipose samples from 228 male mice was hybridized to Affymetrix HT_MG-430A arrays and scanned according to standard Affymetrix protocols.…”

Genetic and hormonal control of hepatic steatosis in female and male mice

“…The experimental design of the HF/ HS feeding study has also been described previously (25). Briefly, the female and male strains included in the HMDP study were maintained on a chow diet (Ralston Purina Co.) until 8 weeks of age before switching over to a HF/HS diet (Research Diet-D12266B; New Brunswick, NJ) for 8 weeks.…”