Role of the NCoR corepressor complex in the development of insulin resistance

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PROGRESS REPORT AND UPDATED RESEARCH PLAN The main goal of this grant was to investigate the role of a transcriptional cofactor, GPS2, and its novel interacting partner, NEURL4/KIAA1787, in obesity-associated inflammatory responses and in the development of insulin resistance. Our original hypothesis was that these two proteins could play a key inhibitory role during the physiological response to insuHn signaling by keeping the NFKB and APi signaling network under negative control in the absence of stimulatory signals. The loss or downregulation of such inhibition may participate in the development of obesity-induced insulin resistance. Three Specific Aims were proposed: i) To define GPS2-dependent gene networks in adipocytes; ii) To investigate the molecular mechanism of GPS2 and KIAA1787 functions in inhibiting JNK-mediated signaling and regulating transcriptional activation mediated by NFKB and APi transcription factors; iii) To test in vivo whether GPS2 and KIAA1787 are relevant for the development of insulin resistance by creating null mice models. Here, for each Aim, I will discuss the progresses made during the K99 phase of the award and describe the future experiments as the original plans have been updated in light ofthe current results.