Abstract
BackgroundThe peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily. The PPAR family consists of three members: PPARα, PPARγ, and PPARδ. PPARδ 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 PPARδ 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.MethodsIn this study, the metabolic role of PPARδ 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 PPARγ activation. To maximize the analytical coverage of the metabolome, 1H-nuclear magnetic resonance (1H-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.ResultsAnalysis by multivariate statistics demonstrated that PPARδ activation profoundly affected glycolysis, gluconeogenesis, the TCA cycle and linoleic acid and α-linolenic acid essential fatty acid pathways.ConclusionsAlthough activation of both PPARδ and PPARγ lead to increased insulin sensitivity and glucose tolerance, PPARδ activation was functionally distinct from PPARγ activation, and was characterized by increased hepatic and peripheral fatty acid oxidative metabolism, demonstrating the distinctive catabolic role of this receptor compared with PPARγ.
Highlights
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily
PPARs heterodimerize with the 9-cis-retinoic acid receptor and bind to target gene peroxisome proliferator response elements, a direct repeat of the sequence AGGTCA separated by one nucleotide [3]
principal components analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) models were built for the individual tissues comparing the control group with the PPARδ agonist treated group and the control group with the ng/ml mg/dl (a) mg/dl (b)
Summary
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily. The physiological ligands of PPARd 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. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control the expression of genes involved in organogenesis, inflammation, cell differentiation, proliferation, and lipid and carbohydrate metabolism [1,2]. A number of synthetic compounds used to treat type 2 diabetes and dyslipidemia are PPAR ligands Upon binding their ligands, PPARs heterodimerize with the 9-cis-retinoic acid receptor and bind to target gene peroxisome proliferator response elements, a direct repeat of the sequence AGGTCA separated by one nucleotide [3]. The receptor is activated by several 14- to 18-carboncontaining polyunsaturated fatty acids, including eicosanoids such as prostaglandin A1, iloprost and carbaprostacyclin [8]
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