PPARγ signaling and emerging opportunities for improved therapeutics

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPAR gamma are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPAR gamma signaling and to develop safer and more effective PPAR gamma-directed therapeutics. In addition to PPAR gamma itself, many PPAR gamma ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPAR gamma responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPAR gamma genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPAR gamma co-activator-1 alpha, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPAR gamma-dependent transcription. Therefore in endothelium, GPR40 and PPAR gamma function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPAR gamma. Thus the role of GPR40 in PPAR gamma signaling may have important implications for drug development. Ligands that strongly activate PPAR gamma, but do not bind to or activate GPR40 may be safer than currently approved PPAR gamma agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPAR gamma, but not ERK1/2, avoiding its harmful effects on PPAR gamma signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock. Published by Elsevier Ltd.