PPAR? ligands are used to control diabetes, but their anti-diabetic actions are puzzling. Here the authors show that phosphorylation of PPAR? 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 PPAR? ligands directly inhibit the effect, and thus support a more normal non-diabetic pattern of gene expression.