Pharmacological activation of peroxisome proliferator-activated receptor ␦/␤ (PPAR␦/␤) improves glucose handling and insulin sensitivity. The target tissues of drug actions remain unclear. We demonstrate here that adenovirus-mediated liverrestricted PPAR␦ 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␦ regulates hepatic metabolic programs through both direct and indirect transcriptional mechanisms partly mediated by its co-activator, PPAR␥ co-activator-1␤. Assessment of the lipid composition reveals that PPAR␦ increases the production of monounsaturated fatty acids, which are PPAR activators, and reduces that of saturated FAs. Despite the increased lipid accumulation, adeno-PPAR␦-infected livers exhibit less damage and show a reduction in JNK stress signaling, suggesting that PPAR␦-regulated lipogenic program may protect against lipotoxicity. The altered substrate utilization by PPAR␦ 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␦ controls hepatic energy substrate homeostasis by coordinated regulation of glucose and fatty acid metabolism, which provide a molecular basis for developing PPAR␦ agonists to manage hyperglycemia and insulin resistance.

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