Increased hepatic oxidative metabolism distinguishes the action of Peroxisome proliferator-activated receptor [delta] from Peroxisome proliferator-activated receptor [gamma] in the ob / ob mouse

Background The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily. The PPAR family consists of three members: PPAR[alpha], PPAR[gamma], and PPAR[delta]. PPAR[delta] controls the transcription of genes involve...

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Published inGenome medicine Vol. 1; p. 115
Main Authors Hassall, David G, Griffin, Julian L, Haselden, John N, Winegar, Deborah A, Roberts, Lee D, Nicholls, Andrew W
Format Journal Article
LanguageEnglish
Published BioMed Central Ltd 07.12.2009
Subjects
Amino acids
Biological products
Cholesterol
Dextrose
DNA binding proteins
Genetic aspects
Glucose
Glycolysis
Health aspects
Insulin resistance
Linolenic acids
Medical research
Medicine, Experimental
Metabolites
Monounsaturated fatty acids
Type 2 diabetes
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Summary:Background The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily. The PPAR family consists of three members: PPAR[alpha], PPAR[gamma], and PPAR[delta]. PPAR[delta] controls the transcription of genes involved in multiple physiological pathways, including cellular differentiation, lipid metabolism and energy homeostasis. The receptor is expressed almost ubiquitously, with high expression in liver and skeletal muscle. Although the physiological ligands of PPAR[delta] remain undefined, a number of high affinity synthetic ligands have been developed for the receptor as a therapeutic target for type 2 diabetes mellitus, dyslipidemia and the metabolic syndrome. Methods In this study, the metabolic role of PPAR[delta] activation has been investigated in liver, skeletal muscle, blood serum and white adipose tissue from ob/ob mice using a high affinity synthetic ligand and contrasted with PPAR[gamma] activation. To maximize the analytical coverage of the metabolome, .sup.1.sup.H-nuclear magnetic resonance (.sup.1.sup.H-NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-mass spectrometry (UPLC-MS) were used to examine metabolites from tissue extracts. Results Analysis by multivariate statistics demonstrated that PPAR[delta] activation profoundly affected glycolysis, gluconeogenesis, the TCA cycle and linoleic acid and [alpha]-linolenic acid essential fatty acid pathways. Conclusions Although activation of both PPAR[delta] and PPAR[gamma] lead to increased insulin sensitivity and glucose tolerance, PPAR[delta] activation was functionally distinct from PPAR[gamma] activation, and was characterized by increased hepatic and peripheral fatty acid oxidative metabolism, demonstrating the distinctive catabolic role of this receptor compared with PPAR[gamma].
ISSN:1756-994X
1756-994X