MAP激酶在FGF21/PPARγ/脂联素信号传导过程中所扮演的角色

ibroblast growth factor (FGF21)is a type of hormone secreted mainly from hepatocytes with many metabolic regulatory functions. Animal experiment studies indicated that FGF21 is a novel target agent of anti-diabetic drug with an extremely entensive application prospect for its positive bio-functions including attenuating hypertension, improving lipid dysfunction, inhibiting obesity and fatty liver disease.Our recent studies demonstrated that the insulin-sensitizing adipokine adiponectin is a downstream effector of FGF21. Furthermore, FGF21 regulated the expression and secretion of adiponectin by activating peroxisome proliferator-activated receptor-γ（PPARγ）, and then presented its anti-diabetic bio-effect. However, How FGF21 regulated the pathway of the PPARγ-adiponectin axis remains unclear. In this study, we will explore and answer next several questions made use of the JNK1 knockout and db/db mice: (1) whether c-jun terminal kinase 1(JNK1) is involved in the regulation of FGF21-PPARγ signal pathway, and then influenced the effect of FGF21 against diabetes in mice? (2) Whether the deficiency of extracellular signal-regulated kinases1/2(Erk1/2) will affect the bio-effect of FGF21 against diabetes in mice? (3) To clarify the molecular mechanism of JNK1 and Erk1/2 mitogen-activated protein kinase to regulate the FGF21-PPARr-adiponectin signal axis based on in vitro experiments. Our study will provides a new evidence and theory for developing anti-diabetic drug on basis of FGF21 and its molecular signal pathway.

FGF21是近年来发现的一种最具抗糖尿病特性的新型蛋白。我们发现，FGF21通过过氧化物酶体增殖物激活受体γ（PPARγ）调节脂联素的表达，从而发挥其抗糖尿病的生物学效应。然而，FGF21是如何调节PPARγ-脂联素通路？这有待于深入研究。在肥胖引发相关疾病中，丝裂原活化蛋白(MAP)激酶JNK1和Erk1/2等家族成员与胰岛素抵抗密切相关，并参与肝脏脂肪代谢调控。本项目以JNK1 敲除和db/db糖尿病小鼠为模型，（1）观察JNK1 MAP激酶对FGF21抗糖尿病小鼠病变的影响；（2）观察Erk1/2 MAP激酶失活对FGF21抗糖尿病小鼠病变的影响；（3）从离体细胞角度探索JNK1、Erk1/2 MAP对FGF21-PPARγ-脂联素分子信号传导的影响。本项目的完成将有助于进一步阐明FGF21调节PPARγ的具体分子作用机制，为开发以FGF21为靶点的新型抗糖尿病新药提供实验理论基础。

FGF21是近年来发现的一种最具抗糖尿病特性的新型蛋白。我们的研究发现，FGF21通过过氧化物酶体增殖物激活受体γ（PPARγ）调节脂联素的表达与分泌，从而发挥其降低血糖、增加胰岛素敏感性等多种生物功效。然而，FGF21是如何调节PPARγ-脂联素通路，发挥其抗糖尿病的生物功能？这有待于深入探索。在肥胖引发相关疾病发病中，丝裂原活化蛋白激酶JNK1和Erk1/2等家族成员与机体内胰岛素抵抗密切相关，并直接参与肝脏脂肪代谢调控状况。本课题通过动物与细胞相结合的方式，以db/db糖尿病小鼠和HFD诱导的糖尿病小鼠为模型，探索FGF21调控PPARγ-脂联素信号通路的分子机制：（1）观察JNK1 MAP激酶失活对FGF21抗糖尿病小鼠病变的影响；（2）观察Erk1/2 MAP激酶失活对FGF21抗糖尿病小鼠病变的影响；（3）从离体细胞角度探索JNK1、Erk1/2 MAP激酶缺失对FGF21-PPARγ-脂联素信号传导及脂联素表达分泌的影响。我们的研究结果显示：（1）FGF21具有调节机体血糖平稳及改善异常血脂的生物功能，但Erk1/2对FGF21调节PPARγ-aidponectin信号通路并无直接的调控作用；（2）FGF21可以通过抑制脂肪细胞JNK1/2的表达，部分介导调节PPARγ-aidponectin信号通路从而发挥其降血糖的生物学效应。.此外，我们还探索了FGF21抗Ang II诱导高血压和血管损伤的病理机制。结果发现：FGF21基因缺失加速Ang II诱导的血压上升和血管损伤，而给予AAV-FGF21病毒，这些负面效应被明显抑制。在分子机制方面，我们的结果显示，FGF21通过调节脂肪细胞和肾脏相关细胞的ACE2表达，进而激活其下游Angiotensin-1-7/MAS信号通路，从而达到降低Ang II在各个器官的滴度，最终达到降血压和血管保护效应。. 以上研究结果提示，FGF21作为一种新型具有调节机体脂糖代谢、胰岛素增敏等多种生物学功效的细胞因子，在糖尿病及高血压病变过程中扮演着重要的角色，这些为开发具有多器官调节功能的新型抗高血压药及抗糖尿病药物提供了新的靶点和实验理论基础。