FGFR1通过调节炎症介导高脂诱导的胰岛素抵抗的作用机制研究

Chronic inflammation induced by saturated fatty acids in obesity is a critical pathological process of insulin resistance. Fibroblast growth factor receptor 1 (FGFR1) is one of the most important targets for tumor targeted therapy. Recently, there were increasing evidences that FGFR1 was involved in inflammatory disorders. Our previous studies showed that insulin resistance in ob/ob mice was significantly attenuated by FGFR1 inhibitor AZD4547. In vitro, AZD4547 treatment could significantly inhibited palmitic acid (PA)-induced inflammatory response in macrophages. Thus, we hypothesize that FGFR1 plays an important role in the pathogenesis of inflammation and insulin resistance. In this project, we will clarify the molecular mechanism that PA active FGFR1 to mediated inflammation and insulin resistance at the cellular level; demonstrate FGFR1 can be prevention and treatment target for insulin resistance-related diseases at animal level using mice with FGFR1-specific knockout in fat and liver tissue; explore the relation between insulin resistance and FGFR1 expression and activation in abdominal fat at clinical level. The project will clarify the role of FGFR1 in insulin resistance and its molecular mechanism that mediates hyperlipidemia-induced inflammation, providing new drug and new target for the prevention and treatment of insulin-related diseases.

肥胖过程中的饱和脂肪酸引起慢性炎症是介导胰岛素抵抗的重要病理过程。成纤维生长因子受体1（FGFR1）是目前肿瘤靶向治疗的重要靶点之一，但近年发现FGFR1还可以介导一些炎症相关疾病。我们前期研究发现： FGFR1抑制剂AZD4547显著改善ob/ob小鼠的胰岛素抵抗；在体外，AZD4547能够明显抑制棕榈酸（PA）引起巨噬细胞的炎症反应。我们假设，FGFR1在炎症-胰岛素抵抗的病理进程中有着重要的介导作用。本项目中，我们拟在细胞层面阐明PA激活FGFR1介导炎症反应和胰岛素抵抗的上下游分子机制；动物层面利用脂肪和肝脏组织FGFR1特异性敲除小鼠明确FGFR1可作为胰岛素抵抗相关疾病的防治靶点；在临床层面初步探讨肥胖患者腹部脂肪中的FGFR1表达和激活与胰岛素抵抗的相关性。项目将明确FGFR1在胰岛素抵抗中的作用及其介导高血脂炎症的分子机制，为防治胰岛素相关疾病提供新药物和新靶点。

与肥胖相关的胰岛素抵抗是一个世界范围内日益严重的健康问题。最近有报道称，FGFR 信号通路参与了慢性代谢性疾病。然而，FGFR信号通路与胰岛素抵抗之间的联系尚不清楚．在本研究中，我们探讨了 FGFR 抑制剂 AZD4547 在肥胖相关胰岛素抵抗发展中的作用。我们的结果显示，AZD4547 处理改善了肥胖诱导的 C57BL/6J 小鼠、ApoE敲除小鼠和 ob/ob小鼠的胰岛素抵抗。此外，AZD4547 恢复了胰岛素对肝细胞和前脂肪细胞葡萄糖摄取的影响，并减轻了脂肪组织和肝组织中肥胖诱导的炎症。因此，我们的研究表明，FGFR 信号通路可能是胰岛素抵抗的中心驱动因素，并是未来-一个有吸引力的治疗靶点．