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null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome
1 Biochemistry, University of Cambridge, Cambridge, Cambs, United Kingdom
2 Selcia, Ongar, Essex, United Kingdom
3 University Laboratory of Physiology, University of Oxford, Oxford, Oxfordshire, United Kingdom
4 Waters Corporation, Manchester, Lancs, United Kingdom
5 Biochemistry, Cambridge University, Cambridge, United Kingdom
* To whom correspondence should be addressed. E-mail: jlg40{at}mole.bio.cam.ac.uk.
The mobilisation 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 
-oxidation in the liver, in part under the regulation of peroxisome proliferator-activated receptor alpha (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 which accompany diabetes, dyslipidaemia 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 month 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 analysed 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.
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