TORC2-dependent regulation of gluconeogensis

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DESCRIPTION (provided by applicant): Glucose homeostasis is maintained by coordinating glucose metabolism in skeletal muscle, lipid storage in adipose tissue, and glucose production in the liver. Insulin and glucagon are central hormone regulators of glucose homeostasis. Glucagon initiates the gluconeogenic program in hepatocytes by activating the cAMP signaling pathway, while insulin inhibits hepatic glucose output. Our recent experiments identifying a new component of the cAMP pathway, TORCs (Transducers of Regulated CREB), have established that cAMP signaling is more sophisticated than previously recognized and provide new insights into glucose homeostasis. Collectively, recent studies have demonstrated that insulin, glucagon, and energy signals converge on TORC2 phosphorylation to modulate glucose output via CREB-mediated hepatic gene expression. However, the specific nuclear actions of TORC2 are unknown. Thus, the mechanisms involved in differentiating TORC2-transmitted signals are of important biological and clinical interest. We have identified and confirmed a novel physical interaction between endogenous TORC2 and the RNA binding protein NONO (p54nrb). NONO regulates pre-mRNA processing and, importantly, our Preliminary Studies have demonstrated that NONO is a necessary and non- redundant component of the cAMP signaling pathway. Our findings support the hypothesis that TORC2 controls gene expression and protein production via alternative splicing of cAMP target genes. We will test the hypothesis that NONO is a required component of hepatic gluconeogenesis and will define the mechanism by which TORC2 and NONO control pre-mRNA processing to maintain glucose homeostasis. Type 2 diabetes has reached pandemic proportions with approximately 20 million individuals affected in the United States alone. Individuals suffering from type 2 diabetes either do not produce enough insulin or more commonly their cells become insensitive to insulin signaling resulting in an imbalance in glucose homeostasis. By studying the mechanisms of regulation of key gluconeogenic genes we will uncover key therapeutic targets.