Early Metabolic Adaptation in C57BL/6 Mice Resistant
to High Fat Diet Induced Weight Gain Involves an Activation of Mitochondrial
Oxidative Pathways
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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 (<i>n</i> =
80) were fed a standard chow diet for 7 days prior to randomization
into a high-fat (HF) (<i>n</i> = 56) or a low-fat (LF) (<i>n</i> = 24) diet group. The <sup>1</sup>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 (<i>n</i> = 10) and SR mice
(<i>n</i> = 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