Identification Of A Novel Selective Agonist Of Ppar Gamma With No Promotion Of Adipogenesis And Less Inhibition Of Osteoblastogenesis

Nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays an important role in the regulation of glucose homeostasis and lipid metabolism. However, current PPAR gamma-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified a small molecular compound, F12016, as a selective PPAR gamma agonist by virtual screening, which showed moderate PPAR gamma agonistic activity and binding ability for PPAR gamma. F12016 did not activate other PPAR subtypes at 30 mu M and selectively modulated PPAR gamma target gene expression. In diabetic KKAy mice, F12016 had insulin-sensitizing and glucose-lowering properties, and suppressed weight gain. In vitro, F12016 effectively increased glucose uptake and blocked cyclin-dependent kinase 5-mediated phosphorylation of PPAR gamma at Ser273, but slightly triggered adipogenesis and less inhibited osteoblastogenesis than rosiglitazone. Moreover, compared with the full agonist rosiglitazone, F12016 had a distinct group of coregulators and a different predicted binding mode for the PPAR gamma ligand-binding domain. A site mutation assay confirmed the key epitopes, especially Tyr473 in AF-2. In summary, our study shows that F12016 is a non-TZD, novel selective PPAR gamma agonist without the classical lipogenic side effects, which may provide a new structural strategy for designing PPAR gamma ligands with advantages over TZDs.