Peroxisome proliferator-activated receptor gamma (PPAR gamma) and ligand choreography: newcomers take the stage.

Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor gamma (PPAR gamma) full agonists that have been widely used in the treatment of type 2 diabetes Mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed Mechanisms for the antidiabetic activity of PPAR gamma agonists, consisting of PPAR gamma Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPAR gamma ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPAR gamma ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPAR gamma-Mediated antidiabetic drugs.