Targeting the hepatic adropin signaling pathway in obesity

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PROJECT SUMMARY/ABSTRACT Obesity is the second leading cause of preventable death in the United States. Obesity is a complex nutritional and genetic disorder that is driven by energy imbalances, and serves as a fundamental risk factor in various pathologies including coronary artery disease, diabetes, non-alcoholic fatty liver disease, and atherosclerosis. The cellular and molecular mechanisms that drive obesity-related disease in different tissues are not fully elucidated, and this represents an impediment to the development of effective and efficient treatments. Adropin is a recently characterized liver- and brain-derived peptide hormone that exerts powerful effects on fuel substrate metabolism in peripheral tissues. Adropin levels are significantly reduced in obese and diabetic human subjects, and this decrease is linked to increased adiposity and impaired glucose homeostasis. Furthermore, adropin depletion has been linked with the development of liver-associated obesity diseases such as NAFLD and NASH. In this fellowship application, we will determine the molecular signaling pathways underlying adropin function in liver fuel metabolism, and investigate its protective effects against NAFLD and NASH. In Aim 1, we will determine how adropin associates with the cell membrane receptor GPR19 to regulate hepatocyte fuel metabolism. In Aim 2, we will determine if GPR19 is necessary for the protective effects of adropin against hepatic injury. By combining cutting-edge metabolic techniques and a comprehensive training plan, this fellowship will allow me to prepare for the next stage of my career in metabolic research and scientific education.