title: Early metabolic adaptation in C57BL/6 mice resistant to high fat diet induced weight gain involves an activation of mitochondrial oxidative pathways.
abstract: We investigated the short-term (7 days) and long-term (60 days) metabolic effect of high fat diet induced obesity (DIO) and weight gain in isogenic C57BL/6 mice and examined the specific metabolic differentiation between mice that were either strong-responders (SR), or non-responders (NR) to weight gain. Mice (n = 80) were fed a standard chow diet for 7 days prior to randomization into a high-fat (HF) (n = 56) or a low-fat (LF) (n = 24) diet group. The (1)H NMR urinary metabolic profiles of LF and HF mice were recorded 7 and 60 days after the diet switch. On the basis of the body weight gain (BWG) distribution of HF group, we identified NR mice (n = 10) and SR mice (n = 14) to DIO. Compared with LF, HF feeding increased urinary excretion of glycine conjugates of β-oxidation intermediate (hexanoylglycine), branched chain amino acid (BCAA) catabolism intermediates (isovalerylglycine, α-keto-β-methylvalerate and α-ketoisovalerate) and end-products of nicotinamide adenine dinucleotide (NAD) metabolism (N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide) suggesting up-regulation of mitochondrial oxidative pathways. In the HF group, NR mice excreted relatively more hexanoylglycine, isovalerylglycine, and fewer tricarboxylic acid (TCA) cycle intermediate (succinate) in comparison to SR mice. Thus, subtle regulation of ketogenic pathways in DIO may alleviate the saturation of the TCA cycle and mitochondrial oxidative metabolism.
authors.affiliation: Section of Biomolecular medicine, Division of Surgery and Cancer, Faculty of Medicine, Imperial College London , Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Boulangé
authors.forename: Sandrine P
authors.initials: SP
authors.lastname: Claus
authors.forename: Chieh J
authors.initials: CJ
authors.lastname: Chou
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Collino
authors.forename: Ivan
authors.initials: I
authors.lastname: Montoliu
authors.forename: Sunil
authors.initials: S
authors.lastname: Kochhar
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Serge
authors.initials: S
authors.lastname: Rezzi
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Marc E
authors.initials: ME
authors.lastname: Dumas
authors.forename: François-Pierre J
authors.initials: FP
authors.lastname: Martin
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D045782:Hemiterpenes; D007651:Keto Acids / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D010084:Oxidation-Reduction; D019802:Succinic Acid / Q000378:metabolism; D014556:Urine / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D045782:Hemiterpenes; D007651:Keto Acids; D009243:NAD; C016211:alpha-keto-beta-methylvaleric acid; C001505:alpha-ketoisovalerate; D019802:Succinic Acid