A Second Chance for a PPARγ Targeted Therapy?

Abstract

### Antidiabetic Actions of a Non-Agonist PPARγ Ligand Blocking Cdk5-Mediated Phosphorylation Choi et al Nature . 2011;477:477–481. A new class of non-agonist ligands target the transcription factor PPARγ and promote expression of insulin-sensitizing adipokines. They have potent antidiabetic actions, yet they lack several of the adverse effects commonly associated with thiazolidinediones. The ligands may represent a new class of anti-diabetes medications that preserve the most beneficial effects of PPARγ activation without imparting major side effects, which have limited the clinical usefulness of thiazolidinediones . Once thought to be a magic bullet for the treatment of type 2 diabetes, thiazolidinedione (TZD) drugs such as rosiglitazone and pioglitazone are now recognized to have adverse effects, which have limited their clinical usefulness. TZDs were originally thought to improve insulin sensitivity by robustly activating the transcriptional activity of the ligand-activated nuclear receptor PPARγ. A study by the Spiegelman laboratory published in the July 22, 2010 issue of Nature revealed that rosiglitazone also inhibits the obesity-induced phosphorylation of PPARγ by the cyclin-dependent kinase 5 (Cdk5).1 The inhibition of CDK5-mediated phosphorylation of PPARγ could also be mediated by PPARγ ligands, which lack full agonist activity suggesting a novel action of TZDs on PPARγ. Now, in the September 22, 2011 issue of Nature , the same research team reports that a new class of PPARγ ligands, which do not act as classical agonists as they lack robust transcriptional activation, effectively block Cdk5-mediated phosphorylation of PPARγ.2 Importantly, these compounds have potent antidiabetic actions, but they do not cause fluid retention nor inhibit bone formation, major adverse effects of TZDs. The study provides an important proof-of-principle that new non-TZD drugs targeting PPARγ could be designed that preserve its most beneficial actions while eliminating its most detrimental side effects. PPARγ is the target of the TZD class of antidiabetic agents, which improves glycemic control by increasing sensitivity to insulin. An ideal type 2 diabetes drug …