PPARγ– A New Twist in the Tale

Obesity and related disorders such as diabetes have reached epidemic proportions. Although the anti-diabetic thiazolidinediones (glitazones) are effective insulin sensitizers, some members of the class have been withdrawn or had their use restricted because of safety concerns. Increased responsiveness to insulin is believed to be mediated by activation of the nuclear receptor, PPARγ but differences in clinically important side effects suggest subtle differences in pharmacology, even amongst full agonists.

Researchers at the Scripps Research Institute and the Dana-Farber Cancer Institute at Harvard University have now shown that cyclin-dependent kinase 5 (Cdk5) in adipose tissue is activated in obese mice fed a high-fat diet, resulting in phosphorylation of PPARγ. This has no effect on the adipogenic capacity of PPARγ but does alter the expression of a large number of obesity-related genes, including a reduction in expression of the insulin-sensitizing adipokine, adiponectin. Phosphorylation of PPARγ by Cdk5 was blocked both in vitro and in vivo by the full agonist, rosiglitazone, and by the partial agonist, MRL-24, leading to increased adiponectin production. The anti-diabetic effect of rosiglitazone in obese patients was also found to be closely associated with inhibition of PPARγ phosphorylation, suggesting that this may be a mechanism of insulin resistance. The authors of the study, which is published in the journal Nature, suggest that drugs that inhibit PPARγ phosphorylation by Cdk5, without necessarily activating the receptor, may provide an improved generation of anti-diabetic drugs.