A metabolomic investigation of mouse models of atherosclerosis and the metabolic syndrome

1n NMR spectroscopy and gas chromatography (GC) based metabolimics approaches were used to characterize the metabolic profiles of a selection of mouse models of atherosclerosis, including the wildtype C57BL/6 mice, the low-density lipoprotein receptor null (LDLR-/-) mice, and the Apolipoprotein E null (ApoE-/-) mice. The LDLR-/- mice demonstrated a profound perturbation in lipid and choline metabolism, notably the choline oxidation pathway, which results in reduced concentrations of choline derivatives in urine. A consistent change in this pathway was also observed in the ApoE-/- mice. The ApoE-/- mice exhibited significant changes in energy metabolism, favouring the utilisation of fatty acids for energy production. These findings were also compared with the ApoE-/- mice that are haplodeficient for the Ataxia telangiectasia mutated (ATM) gene. The ATM+/-/ApoE-/- mice demonstrated accelerated atherosclerosis and more severe abnormalities in energy metabolism, as compared with the ATM+/+/ApoE-/- mice. Finally, a metabolomic study on an inducible Akt1 transgenic mouse model was conducted. These mice exhibit inducible muscle hypertrophy, as well as a significant reduction in fat mass. The muscle-specific Akt1 activation caused increased glycolysis in gastronemius muscle, as well as increased gluconeogenesis, glycogenolysis and ketogenesis in the liver of the mice. These data demonstrate how hypertrophic muscle affects systemic metabolism, and influences distant organs to feed its active cell growth. The studies demonstrated the impact of a muscle-specific Akt1 activation on systemic metabolism, which leads to a reduction in risks associated with cardiovascular disease.EThOS - Electronic Theses Online ServiceGBUnited Kingdo