Genetic Control of Obesity and Gut Microbiota Composition in Response to High-Fat, High-Sucrose Diet in Mice

Abstract

SUMMARY Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that is not accounted for by food intake and provide evidence for a genetically determined set-point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity.

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).…”

Open Chromatin Profiling in Mice Livers Reveals Unique Chromatin Variations Induced by High Fat Diet

“…Body fat percentage and body weight were tracked as described previously (14). The animal protocols for the study were approved by the Institutional Care and Use Committee (IACUC) at the UCLA and the City of Hope.…”

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

“…The aim of this study was to describe the sex difference in hepatic steatosis in a population of diverse inbred strains of mice known as the Hybrid Mouse Diversity Panel (HMDP) fed a high-fat high-sucrose (HF/HS) diet (22). The use of the HMDP provided a rich genetic background to assess both the phenotypes and genetic interactions associated with hepatic TG concentration in mice of both sexes.…”