Portal de Periódicos da CAPES

Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5

2010; Nature Portfolio; Volume: 466; Issue: 7305 Linguagem: Inglês

10.1038/nature09291

1476-4687

Jang Hyun Choi, Alexander S. Banks, Jennifer L. Estall, Shingo Kajimura, Pontus Boström, Dina Laznik, Jorge L. Ruas, Michael J. Chalmers, Theodore M. Kamenecka, Matthias Blüher, Patrick R. Griffin, Bruce M. Spiegelman,

Adipose Tissue and Metabolism

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 (peroxisome proliferator-activated receptor γ), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARγ 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 by Cdk5 is blocked by anti-diabetic PPARγ 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 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 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. Thiazolidinedione antidiabetics such as rosiglitazone and pioglitazone are known to act through the nuclear receptor PPARγ, but some aspects of the mechanism of their insulin-sensitizing effect remain puzzling. Choi et al. now report that phosphorylation of PPARγ by Cdk5 is linked to obesity induced by high-fat feeding in mice. Several antidiabetic PPARγ ligands directly inhibit this action of Cdk5 on PPARγ, and thus support a more normal non-diabetic pattern of gene expression. In addition, inhibition of this PPARγ phosphorylation in humans by rosiglitazone is closely associated with its antidiabetic effects. This unusual pharmacology suggests a new model for a Cdk5–PPARγ link in the pathogenesis of obesity and diabetes, and for the therapeutic action of PPARγ ligands in these disorders as well as in metabolic syndrome, a combination of disorders that increases the risk of cardiovascular disease and diabetes. PPARγ ligands are used to control diabetes, but their anti-diabetic actions are puzzling. Here the authors show that phosphorylation of PPARγ by cyclin-dependent kinase 5 (Cdk5) in mice is linked to obesity induced by high-fat feeding, and that inhibition of the effect in humans by the drug rosiglitazone is closely associated with its anti-diabetic effects. Several anti-diabetic PPARγ ligands directly inhibit the effect, and thus support a more normal non-diabetic pattern of gene expression.