title: Phylometabonomic patterns of adaptation to high fat diet feeding in inbred mice.
abstract: Insulin resistance plays a central role in type 2 diabetes and obesity, which develop as a consequence of genetic and environmental factors. Dietary changes including high fat diet (HFD) feeding promotes insulin resistance in rodent models which present useful systems for studying interactions between genetic background and environmental influences contributing to disease susceptibility and progression. We applied a combination of classical physiological, biochemical and hormonal studies and plasma (1)H NMR spectroscopy-based metabonomics to characterize the phenotypic and metabotypic consequences of HFD (40%) feeding in inbred mouse strains (C57BL/6, 129S6, BALB/c, DBA/2, C3H) frequently used in genetic studies. We showed the wide range of phenotypic and metabonomic adaptations to HFD across the five strains and the increased nutrigenomic predisposition of 129S6 and C57BL/6 to insulin resistance and obesity relative to the other strains. In contrast mice of the BALB/c and DBA/2 strains showed relative resistance to HFD-induced glucose intolerance and obesity. Hierarchical metabonomic clustering derived from (1)H NMR spectral data of the strains provided a phylometabonomic classification of strain-specific metabolic features and differential responses to HFD which closely match SNP-based phylogenetic relationships between strains. Our results support the concept of genomic clustering of functionally related genes and provide important information for defining biological markers predicting spontaneous susceptibility to insulin resistance and pathological adaptations to fat feeding.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Fearnside
authors.forename: Marc-Emmanuel
authors.initials: ME
authors.lastname: Dumas
authors.forename: Alice R
authors.initials: AR
authors.lastname: Rothwell
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilder
authors.forename: Olivier
authors.initials: O
authors.lastname: Cloarec
authors.forename: Ayo
authors.initials: A
authors.lastname: Toye
authors.forename: Christine
authors.initials: C
authors.lastname: Blancher
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Roger
authors.initials: R
authors.lastname: Tatoud
authors.forename: Richard H
authors.initials: RH
authors.lastname: Barton
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D007333:Insulin Resistance; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008660:Metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity; D010641:Phenotype; D010802:Phylogeny; D013045:Species Specificity
chemical_list: D004041:Dietary Fats