Role of Peroxisome Proliferator-activated Receptor δ/β in Hepatic Metabolic Regulation

Pharmacological activation of peroxisome proliferator-activated receptor delta/beta (PPAR delta/beta) improves glucose handling and insulin sensitivity. The target tissues of drug actions remain unclear. We demonstrate here that adenovirus-mediated liver-restricted PPAR delta activation reduces fasting glucose levels in chow-and high fat-fed mice. This effect is accompanied by hepatic glycogen and lipid deposition as well as up-regulation of glucose utilization and de novo lipogenesis pathways. Promoter analyses indicate that PPAR delta regulates hepatic metabolic programs through both direct and indirect transcriptional mechanisms partly mediated by its co-activator, PPAR gamma co-activator-1 beta. Assessment of the lipid composition reveals that PPAR delta increases the production of monounsaturated fatty acids, which are PPAR activators, and reduces that of saturated FAs. Despite the increased lipid accumulation, adeno-PPAR delta-infected livers exhibit less damage and show a reduction in JNK stress signaling, suggesting that PPAR delta-regulated lipogenic program may protect against lipotoxicity. The altered substrate utilization by PPAR delta also results in a secondary effect on AMP-activated protein kinase activation, which likely contributes to the glucose-lowering activity. Collectively, our data suggest that PPAR delta controls hepatic energy substrate homeostasis by coordinated regulation of glucose and fatty acid metabolism, which provide a molecular basis for developing PPAR delta agonists to manage hyperglycemia and insulin resistance.