Ligand-dependent Interaction of PPARδ with T Cell Protein Tyrosine Phosphatase 45 Enhances Insulin Signaling.

Peroxisome proliferator-activated receptor (PPAR) delta plays a pivotal role in metabolic homeostasis through its effect on insulin signaling. Although diverse genomic actions of PPAR delta are postulated, the specific molecular mechanisms whereby PPARd controls insulin signaling have not been fully elucidated. We demonstrate here that short-term activation of PPAR delta results in the formation of a stable complex with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform. This interaction of PPAR delta with TCPTP45 blocked translocation of TCPTP45 into the cytoplasm, thereby preventing its interaction with the insulin receptor, which inhibits insulin signaling. Interaction of PPAR delta with TCPTP45 blunted interleukin 6-induced insulin resistance, leading to retention of TCPTP45 in the nucleus, thereby facilitating deactivation of the signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3) signal. Finally, GW501516-activated PPAR delta improved insulin signaling and glucose intolerance in mice fed a high-fat diet through its interaction with TCPTP45. This novel interaction of PPAR delta constitutes the most upstream component identified of the mechanism downregulating insulin signaling.