title: Nutrigenomics of high fat diet induced obesity in mice suggests relationships between susceptibility to fatty liver disease and the proteasome.
abstract: Nutritional factors play important roles in the etiology of obesity, type 2 diabetes mellitus and their complications through genotype x environment interactions. We have characterised molecular adaptation to high fat diet (HFD) feeding in inbred mouse strains widely used in genetic and physiological studies. We carried out physiological tests, plasma lipid assays, obesity measures, liver histology, hepatic lipid measurements and liver genome-wide gene transcription profiling in C57BL/6J and BALB/c mice fed either a control or a high fat diet. The two strains showed marked susceptibility (C57BL/6J) and relative resistance (BALB/c) to HFD-induced insulin resistance and non alcoholic fatty liver disease (NAFLD). Global gene set enrichment analysis (GSEA) of transcriptome data identified consistent patterns of expression of key genes (Srebf1, Stard4, Pnpla2, Ccnd1) and molecular pathways in the two strains, which may underlie homeostatic adaptations to dietary fat. Differential regulation of pathways, including the proteasome, the ubiquitin mediated proteolysis and PPAR signalling in fat fed C57BL/6J and BALB/c suggests that altered expression of underlying diet-responsive genes may be involved in contrasting nutrigenomic predisposition and resistance to insulin resistance and NAFLD in these models. Collectively, these data, which further demonstrate the impact of gene x environment interactions on gene expression regulations, contribute to improved knowledge of natural and pathogenic adaptive genomic regulations and molecular mechanisms associated with genetically determined susceptibility and resistance to metabolic diseases.
authors: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Helen
authors: H
authors: Waller-Evans
authors: Christophe
authors: C
authors: Hue
authors: Jane
authors: J
authors: Fearnside
authors: Alice R
authors: AR
authors: Rothwell
authors: Helen E
authors: HE
authors: Lockstone
authors: Sophie
authors: S
authors: Caldérari
authors: Steven P
authors: SP
authors: Wilder
authors: Jean-Baptiste
authors: JB
authors: Cazier
authors: James
authors: J
authors: Scott
authors: Dominique
authors: D
authors: Gauguier
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D059305:Diet, High-Fat; D004198:Disease Susceptibility; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D054647:Nutrigenomics; D009765:Obesity / Q000150:complications* / Q000209:etiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D046988:Proteasome Endopeptidase Complex; D005947:Glucose