biostudies-literatureParks BWNICHD NIH HHSNIDDK NIH HHSHoward Hughes Medical InstituteNHLBI NIH HHSNIGMS NIH HHS141-52https://www.ebi.ac.uk/biostudies/studies/S-EPMC3545283biostudies-literatureUnknown17(1)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 are 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.Cell metabolismGenetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.PMC3545283HL30568P01 HL030568T32 GM142607T32 HD007228DK094311HL028481T32 GM008759T32-GM08759R00 HL102223T32-HL69766DP3 DK094311P01 HL028481T32-HD07228T32 HL069766Rau CDNorheim FMehrabian MNam EOrg EEskin EKostem EBennett BJKirby MDrake TAKnight RDrevon CACivelek MPan CParks BWCastellani LWHui STUrsell LKKirchgessner TLusis AJZinker BHe AGargalovic PfalseGenetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.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 are 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.2013-01-01T00:00:00Z2013 Jan2026-04-30T07:31:28.493Z2026-04-07T15:53:04.96ZS-EPMC35452832331228910.1016/j.cmet.2012.12.007