Ligand-Dependent Interaction of PPAR{delta} With T-Cell Protein Tyrosine Phosphatase 45 Enhances Insulin Signaling

Peroxisome proliferator–activated receptor (PPAR) plays a pivotal role in metabolic homeostasis through its effect on insulin signaling. Although diverse genomic actions of PPAR are postulated, the specific molecular mechanisms whereby PPAR controls insulin signaling have not been fully elucidated. We demonstrate here that short-term activation of PPAR results in the formation of a stable complex with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform. This interaction of PPAR with TCPTP45 blocked translocation of TCPTP45 into the cytoplasm, thereby preventing its interaction with the insulin receptor, which inhibits insulin signaling. Interaction of PPAR 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 improved insulin signaling and glucose intolerance in mice fed a high-fat diet through its interaction with TCPTP45. This novel interaction of PPAR constitutes the most upstream component identified of the mechanism downregulating insulin signaling.