The peroxisome proliferator-activated receptors (PPARs) are a subgroup of nuclear receptors activated by fatty acids and eicosanoids. In addition, they are subject to phosphorylation by insulin, resulting in the activation of PPAR␣, while inhibiting PPAR␥ under certain conditions. However, it was hitherto unclear whether the stimulatory effect of insulin on PPAR␣ was direct and by which mechanism it occurs. We now demonstrate that amino acids 1-92 of hPPAR␣ contain an activation function

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... like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPAR␣ revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. The characterization of a strong AF-1 region in PPAR␣, stimulating transcription one-fourth as strongly as the viral protein VP16, is compatible with the marked basal transcriptional activity of this isoform in transfection experiments. However, it is intriguing that the activity of this AF-1 region is modulated by the phosphorylation of two serine residues, both of which must be phosphorylated in order to activate transcription. This is in contrast to PPAR␥2, which was previously shown to be phosphorylated at a single site in a motif that is not homologous to the sites now described in PPAR␣. Although the molecular details involved in the phosphorylation-dependent enhancement of the transcriptional activity of PPAR␣ remain to be elucidated, we demonstrate that the effect of insulin on the AF-1 region of PPAR␣ can be mimicked by the addition of triiodothyronine receptor ␤1, a strong binder of corepressor proteins. In addition, a triiodothyronine receptor ␤1 mutant deficient in interacting with corepressors is unable to activate PPAR␣. These observations suggest that the AF-1 region of PPAR␣ is partially silenced by corepressor proteins, which might interact in a phosphorylation-dependent manner.