Research
Increased hepatic oxidative metabolism distinguishes the action of Peroxisome proliferator-activated receptor δ from Peroxisome proliferator-activated receptor γ in the ob/ob mouse
-
* Corresponding author: Julian L Griffin jlg40@cam.ac.uk
1 Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK
2 GlaxoSmithKline, Investigative Preclinical Toxicology, Park Road, Ware, SG12 0DP, UK
3 GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 277709-3398, USA
Genome Medicine 2009, 1:115 doi:10.1186/gm115
Published: 7 December 2009Abstract
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: 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.
Methods
In 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.
Results
Analysis 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.
Conclusions
Although 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.