Increased hepatic oxidative metabolism distinguishes the action of Peroxisome proliferator-activated receptor δ from Peroxisome proliferator-activated receptor γ in the ob/obmouse

Increased hepatic oxidative metabolism distinguishes the action of Peroxisome proliferator-activated receptor δ from Peroxisome proliferator-activated receptor γ in the ob/obmouse

Genome Medicine, December 2009

19968882

Lee D Roberts, David G Hassall, Deborah A Winegar, John N Haselden, Andrew W Nicholls, Julian L Griffin

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: PPARalpha, PPARgamma, and PPARdelta. PPARdelta 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 PPARdelta 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. In this study, the metabolic role of PPARdelta 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 PPARgamma activation. To maximize the analytical coverage of the metabolome, (1)H-nuclear magnetic resonance ((1)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. Analysis by multivariate statistics demonstrated that PPARdelta activation profoundly affected glycolysis, gluconeogenesis, the TCA cycle and linoleic acid and alpha-linolenic acid essential fatty acid pathways. Although activation of both PPARdelta and PPARgamma lead to increased insulin sensitivity and glucose tolerance, PPARdelta activation was functionally distinct from PPARgamma activation, and was characterized by increased hepatic and peripheral fatty acid oxidative metabolism, demonstrating the distinctive catabolic role of this receptor compared with PPARgamma.