AMPK是细胞和整体能量代谢的监控器，已经成为抗糖尿病以及心血管疾病的潜力新靶点，国际各大制药公司纷纷立项并投入巨大研究力量试图发现AMPK激活剂，用于相关疾病的治疗与干预。本项目研究团队在前期围绕AMPK的活性调控机制与小分子激活剂筛选的研究中，发现了新作用机制激动剂PT1和高生物活性、优良口服生物利用度的衍生物YLF466D。申请本项目旨在前期研究发现YLF466D可有效改善糖尿病db/db小鼠糖脂代谢紊乱基础上，进一步确证YLF466D在糖尿病db/db小鼠以及高脂食物诱导的胰岛素抵抗DIO小鼠的肝脏、骨骼肌以及脂肪组织内对糖代谢和脂肪酸代谢的影响、YLF466D改善糖脂代谢作用对靶点AMPK激活的依赖性验证研究、以及YLF466D在分子水平对AMPK三亚基的调控机制研究，论证新药物靶标AMPK在抗2型糖尿病治疗中的重要作用，并提供靶向AMPK的抗糖尿病先导化合物。

AMP-activated protein kinase (AMPK) is an attractive therapeutic target for type 2 diabetes and metabolic syndrome. AMPK is a highly conserved serine/threonine protein kinase that serves as an energy sensor in metabolism. Once activated, AMPK stimulates catalytic pathways that generate ATP, such as glucose uptake and fatty acid oxidation, whereas it inhibits ATP-consuming anabolic pathways, including the synthesis of hepatic triglycerides, cholesterol, protein and glycogen. Based on our previous studies on autoinhibition regulatory mechanism existing in AMPK α subunit and novel screening method established against inactive AMPK α subunit, we identified PT1 with novel activation mechanism, and more potent and in vivo efficient derivative YLF466D. In this application, we aim to study the efficacy of YLF466D further on diet induced obesity mouse model, and also the molecular activation mode of YLF466D with AMPK hetrotrimer, to prove the relationship of biological activity with the AMPK activation in animal model and functional cell lines, and finally to provide the AMPK agonist as lead compound toward type 2 diabetes and metabolic syndrome.