具有代谢调控功能新型旁分泌生长因子FGFs的发现及降糖机制研究

Fibroblast growth factor (FGF) is an important functional protein family. According to the structure and function, its 18 members are divided into 5 paracrine and 1 endocrine subfamily. For long time, the main function of paracrine FGF was considered for cell proliferation and tissue regeneration. However, the latest research and our study which was supported by NSFC, reported that paracrine FGF1 also has an important hypoglycemic function. Additionally, we demonstrated that the mitogenic and the metabolic activity of FGF1 can be uncoupled by surgically dampening FGF1-FGFR1c dimer stability. This enlightens us to propose two issues: 1) whether the dual functional features of FGF1 are prevalent in all paracrine FGF family members; and 2) how paracrine FGF exerts excellent acute and chronic hypoglycemic functions. For the first question, we plan to screen all paracrine family members to obtain the paracrine FGFs with metabolic regulation, and further reveal their common characteristics. For the second question, based on the previous analysis of tissue distribution and functional characteristics, we will focus on liver targets and intend to elucidate its mechanism of acute and chronic hypoglycemic effects from the aspects of glycogen synthesis and gluconeogenesis. Through this study, we can not only acquire the common features of paracrine FGFs with metabolic function, but also provide theoretical guides for the discovery of the new targets and drugs for the treatment of diabetes.

FGF作为重要的功能蛋白家族，其18个成员按结构和功能分为5个旁分泌和1个内分泌亚家族，长期认为旁分泌FGF功能主要为促细胞增殖和组织再生。但最新的研究报道以及申请人在前一个国自然支持下，研究发现旁分泌FGF1具有重要降糖功能，且FGF1引起的FGFR1c受体二聚化程度是控制其双重功能发挥的关键因素。基于此，本课题提出并拟解决两个问题：1）FGF1双重功能特征是否普遍存在于旁分泌FGF家族；2）旁分泌FGF发挥急慢性降糖的作用机制。针对问题1），本课题拟对旁分泌全家族进行筛选以获取代谢调控旁分泌FGFs成员谱并深入揭示该类FGFs共性特征；针对问题2），基于前期组织分布及功能特征分析，本课题重点聚焦肝脏靶点，拟从糖原合成和糖异生角度阐明其发挥急慢性降糖的作用机制。通过本课题实施，不仅可获取旁分泌FGF产生代谢调控功能共性特征，且为日益严峻的糖尿病治疗新靶点和新药物发现提供理论指引。

旁分泌FGF1具有重要降糖功能是近年来FGF领域的重要发现。因此，进一步探索FGF1的降糖能力是否普遍存在于旁分泌FGF家族具有重要的科学意义。课题组在本基金支持下，基于FGFR二聚化“阈值调控模型”（PNAS, 2020, 17;117(46):29025-29034），对旁分泌FGF家族成员的降糖能力进行筛选，并利用体外糖示踪技术揭示其降糖作用靶器官进而深入分析降糖机制。结果发现，旁分泌FGF4具有显著的降糖能力；骨骼肌是此类蛋白发挥糖代谢调控功能的主要靶器官；而进一步的机制研究表明，FGF4/FGF1通过激活骨骼肌中FGFR1c-Ca2+/CaMKK2-AMPKα信号通路，上调肌肉细胞GLUT4的蛋白表达和转位水平，增强骨骼肌中葡萄糖的摄取能力，从而发挥降糖效应，这一新的分子级联传递过程完全区别于经典胰岛素信号通路，为FGF调控血糖稳态但不导致低血糖的分子机理提供了科学解释（Nat Commun, 2021, 12(1):7256）. 在开展FGF4抗2型糖尿病研究过程中，课题组还发现FGF4可通过激活FGFR4-CaMKK2-AMPK-Caspas6信号轴，对代谢性肝脏炎症进展及NASH相关肝纤维化的病理进展具有显著逆转功效。临床大样本分析，发现非酒精性脂肪肝进展与肝脏组织内源性FGF4的水平呈线性负相关；而肝脏缺失FGF4则会加重肥胖高脂饮食导致的肝脏变性和肝损伤（Hepatology, 2022, 76(4):1105-1120.）。除此之外，本项目还发现FGFR-CaMKK2-AMPK信号通路可介导旁分泌FGF及其改构体对糖尿病心肌病和肾病的改善作用，进一步明确了旁分泌FGF的抗糖尿病及其并发症药理学新功能（Signal Transduct Target Ther, 2021, 6(1):133; EBioMedicine, 2019, 48:462-477）. 总之，本课题基于FGFR二聚化阈值模型，发现CaMKK2-AMPK信号是旁分泌FGF发挥糖脂代谢调控功能的关键分子事件，明确了FGFR调控糖尿病及其并发症的新功能，并据此提出了旁分泌FGF的新型药理学功效，鉴定出糖尿病及其并发症新“药源分子”—— FGF4。