DESCRIPTION (provided by applicant): Obesity is one of the major underlying pathologies for development of insulin resistance and type 2 diabetes. Understanding the molecular mechanisms leading to insulin resistance and type 2 diabetes can provide novel therapeutic approaches for treatment of these debilitating diseases. We have previously shown that increased endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) signaling pathways play a central role in development of insulin resistance and type 2 diabetes in obesity. UPR signaling leads to development of insulin resistance mainly through inositol requiring enzyme-1 (IRE1) mediated activation of c-Jun amino terminal Kinase-1 (JNK1) and consequent phosphorylation of IRS-1 at serine 307. Tuberous sclerosis complex 1 and 2 (TSC1 and 2) genes both encode tumor suppressors. TSC1 and TSC2 are associated in a complex such that deficiency of either gene disrupts the function of this complex, and leads to uncontrolled and aberrant activation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Hyperactivity of mTORC1 pathway causes severe insulin resistance. This is most evident in cells lacking either TSC1 or TSC2. The insulin-stimulated activation of IRS1 and IRS2 is completely blocked in TSC1-/- and TSC2-/- cells together with increased IRS protein degradation. However, the molecular mechanisms responsible for blockade of IRS activity and enhanced degradation are poorly understood. Our preliminary data show that lack of TSC1 or TSC2, and consequent hyperactivity of mTORC1 pathway leads to ER stress and activates the UPR. Blockade of ER stress by a chemical chaperone, 4- phenyl butyric acid (4-PBA), significantly improves insulin signaling and completely blocks IRS-1 degradation, indicating that UPR plays an important role in development of insulin resistance in TSC-deficiency. Our proposal is based on these findings and aims to investigate the in vivo role of JNK-1 and IRS-1ser307 phosphorylation in development of insulin resistance in TSC1-deficient livers. Obesity is a fast growing problem and is one of the most serious threats to human health in the 21st century. Obesity constitutes the highest risk for development of insulin resistance. Insulin resistance predisposes the affected individuals to variety of diseases, including type 2 diabetes and cardiovascular disease. For this reason, understanding the underlying molecular mechanisms of insulin resistance is of crucial importance for new therapeutic opportunities. Our proposal, by using genetically engineered mouse models, aims to investigate the molecular mechanisms of insulin resistance.