Recent studies have suggested glucagon-like peptide-1 (GLP-1) signaling to exert anti-inflammatory effects on endothelial cells, although the precise underlying mechanism remains to be elucidated. In the present study, we investigated whether PPAR gamma activation is involved in the GLP-1-mediated anti-inflammatory action on endothelial cells. When we treated HUVEC cells with 0.2 ng/ml exendin-4, a GLP-1 receptor agonist, endogenous PPAR gamma transcriptional activity was significantly elevated, by approximately 20%, as compared with control cells. The maximum PPAR gamma activity enhancing effect of exendin-4 was observed 12 h after the initiation of incubation with exendin-4. As H89, a PKA inhibitor, abolished GLP-1-induced PPAR gamma enhancement, the signaling downstream from GLP-1 cross-talk must have been involved in PPAR gamma activation. In conclusion, our results suggest that GLP-1 has the potential to induce PPAR gamma activity, partially explaining the anti-inflammatory effects of GLP-1 on endothelial cells. Cross-talk between GLP-1 signaling and PPAR gamma activation would have major impacts on treatments for patients at high risk for cardiovascular disease. (C) 2014 Published by Elsevier Inc.