Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPAR gamma by Cdk5

Abstract

Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARγ 3 (peroxisome proliferator-activated receptor γ 3), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARγ 3 does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPARγ 3 by Cdk5 is blocked by anti-diabetic PPARγ 3 ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPARγ 3 phosphorylation in obese patients by rosiglitazone is very tightly associated with the anti-diabetic effects of this drug. All these findings strongly suggest that Cdk5-mediated phosphorylation of PPARγ 3 may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARγ 3.