Targeting the hepatic adropin signaling pathway in obesity

项目概要/摘要 肥胖是美国可预防死亡的第二大原因。肥胖是一种复杂的营养 以及由能量失衡引起的遗传性疾病，并成为各种疾病的基本风险因素 病理包括冠状动脉疾病、糖尿病、非酒精性脂肪肝和动脉粥样硬化。 在不同组织中驱动肥胖相关疾病的细胞和分子机制尚不完全清楚 已阐明，这对开发有效且高效的治疗方法构成了障碍。阿德罗平 是一种最近鉴定的肝源性和脑源性肽激素，对燃料产生强大的影响 外周组织的底物代谢。肥胖和糖尿病患者的 Adropin 水平显着降低 人类受试者，这种减少与肥胖增加和葡萄糖稳态受损有关。 此外，adropin 消耗与肝脏相关肥胖疾病的发展有关 例如 NAFLD 和 NASH。在本次奖学金申请中，我们将确定分子信号传导途径 adropin 在肝脏燃料代谢中的潜在功能，并研究其对 NAFLD 和 纳什。在目标 1 中，我们将确定 adropin 如何与细胞膜受体 GPR19 结合来调节 肝细胞燃料代谢。在目标 2 中，我们将确定 GPR19 是否对于以下物质的保护作用是必要的： adropin 抗肝损伤。通过结合尖端的代谢技术和全面的训练 计划，这项奖学金将使我为代谢研究和科学职业生涯的下一阶段做好准备 教育。

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.