Thiazolidinedione antidiabetics such as rosi glitazone and pioglitazone are known to act through the nuclear receptor PPARγ, but aspects of their insulin-sensitizing effect remain puzzling. Choi et al. now report that phosphorylation of PPARγ by Cdk5 is linked to obesity induced by a high-fat diet in mice. Several antidiabetic PPARγ ligands directly inhibit this action of Cdk5, and so support a more normal non-diabetic pattern of gene expression. In addition, inhibition of 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 and in metabolic syndrome, a combination of disorders that increases risk of heart disease and diabetes. [Article p. 451; News & Views p. 443; News p. 420; www.nature.com/podcast]
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