PROJECT SUMMARY Obesity-related type 2 diabetes (T2D) is the most common emerging metabolic disease in the US population. Insulin resistance is a key etiological factor of T2D. Adiponectin is an adipocyte-secreted hormone and prevents the development of insulin resistance. Recent studies show that adiponectin decreases the expression of hepatic gluconeogenic enzymes, attenuates glucose production, and enhances the hepatic effects of insulin through the AMP-activated protein kinase (AMPK) pathway. However, the resilience factors that are required to maintain adiponectin-mediated AMPK activation in the liver remain unclear. This proposal is designed to fill gaps in our knowledge concerning the role of NgBR in regulating adiponectin- mediated AMPK activation and hepatic gluconeogenesis, and to determine if preserving hepatic NgBR expression is sufficient to prevent the onset of obesity-related T2D. Recent studies from our laboratory suggest that NgBR plays a previously unrecognized role in maintaining AMPK activation because NgBR binds the farnesylated form of liver kinase B1 (LKB1-farn), a key regulator of AMPK. Preliminary results show that NgBR expression decreases in the liver of diabetic animal models and the liver of T2D obese patients compared to non-T2D obese subjects. NgBR hepatocyte-specific knockout (hepKO) mice showed an increase in fasting glucose levels and further increases plasma glucose to T2D levels after high-fat diet (HFD) feeding. NgBR deficiency in hepatocytes impairs AMPK activation induced by AdipoRon (an agonist of adiponectin receptors). These findings lead us to propose a central hypothesis that NgBR is a resilience factor required for preserving adiponectin-mediated insulin sensitivity and preventing the onset of obesity-caused T2D, and disruption of the NgBR-dependent regulation system in the liver leads to impairing gluconeogenesis regulation and insulin sensitivity. Our overall objectives are to elucidate the molecular mechanisms by which NgBR enhances adiponectin-mediated insulin sensitivity and the roles that NgBR plays in the pathogenesis of insulin resistance and T2D. Delineating the mechanisms by which NgBR regulates LKB1 translocation will allow us to develop new therapeutic strategies for preventing the onset of T2D in obese subjects. Accordingly, we will test our hypothesis with two specific aims. Aim 1. Determine the molecular mechanism by which NgBR regulates LKB1-AMPK activation and adiponectin signaling pathway in the liver. Aim 2. Determine the molecular mechanism by which NgBR regulates insulin signaling and hepatic gluconeogenesis. Successful completion of studies proposed in this proposal will characterize NgBR as a resilience factor for preventing T2D and provide novel insights for T2D prevention or treatment. Our studies will lead to many discoveries that will significantly improve the health of US citizens and others suffering from T2D. Our studies will reveal new concepts and ideas that can be used ...