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A combined ¹H-NMR spectroscopy- and mass spectrometry-based metabolomic study of the PPAR- null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome

¹ Department of Biochemistry, University of Cambridge, Cambridge
² Selcia Limited, Ongar, Essex
³ University Laboratory of Physiology, University of Oxford, Oxford
⁴ Waters Corporation, Manchester, United Kingdom

The mobilization of triacylglycerides from storage in adipocytes to the liver is a vital response to the fasting state in mammalian metabolism. This is accompanied by a rapid translational activation of genes encoding mitochondrial, microsomal, and peroxisomal ß-oxidation in the liver, in part under the regulation of peroxisome proliferator-activated receptor- (PPAR-). A failure to express PPAR- results in profound metabolic perturbations in muscle tissue as well as the liver. These changes represent a number of deficits that accompany diabetes, dyslipidemia, and the metabolic syndrome. In this study, the metabolic role of PPAR- has been investigated in heart, skeletal muscle, liver, and adipose tissue of PPAR- null mice at 1 mo of age using metabolomics. To maximize the coverage of the metabolome in these tissues, ¹H-NMR spectroscopy, magic angle spinning ¹H-NMR spectroscopy, gas chromatography-mass spectrometry, and liquid chromatography-mass spectrometry were used to examine metabolites in aqueous tissue extracts and intact tissue. The data were analyzed by the multivariate approaches of principal components analysis and partial least squares. Across all tissues, there was a profound decrease in glucose and a number of amino acids, including glutamine and alanine, and an increase in lactate, demonstrating that a failure to express PPAR- results in perturbations in glycolysis, the citric acid cycle, and gluconeogenesis. Furthermore, despite PPAR- being weakly expressed in adipose tissue, a profound metabolic perturbation was detected in this tissue.

metabolic profiling; metabonomics; gluconeogenesis; lipid metabolism; metabolic regulation; peroxisome proliferator-activated receptor-

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