GLP-1类似物通过下丘脑小胶质细胞降低DIO大鼠体重调定点机制研究

Obesity has become a worldwide public health problem. At present, there is a big problem of body weight regain after obesity treatment. The GLP-1 analogue liraglutide for obesity treatment has emerged recently with good effect of weight loss and long duration sustained body weight. As in previous studies, the effects of dietary restriction lower body weight but not weight set-point have been found. Releasing diet lead to remarkable weight regains. While liraglutide can significantly reduce body weight and body weight set-point in DIO rats, which sustain a period after drug withdrawal. However, this "Sequelae effect" can not explanation well by direct pharmacological action of GLP-1. Therefore, we hypothesize that in addition to neuromodulation and humoral regulation, GLP-1 analogues may also affect the energy metabolism balance of rats by immunomodulation. And we infer hypothalamic microglia plays an important role in immune regulation. To confirm our hypothesis, we selected DIO rats as Obesity model, using GLP-1 analogue liraglutide and diet restriction as treatment factors respectively. We observe the changes of weight, weight setting point, hypothalamic inflammation and other related indicators in the period of threatment and no-treatment to explore the relationship between GLP-1 and hypothalamic inflammation. Meanwhile, primary rat hypothalamic microglia activation model will be established in vitro, by using wihch the relationship among GLP-1, hypothalamic inflammation and activation of microglia will be well investigated. And we try to explain it from the perspective of neuro-immunoregulation.

肥胖已成为世界性公共卫生问题，目前对于肥胖症的治疗存在体重反弹的难题。新近出现的GLP-1类似物利拉鲁肽有减重效果好，减重后体重稳定的特点。前期研究中我们发现限制饮食可显著降低DIO大鼠体重，但不能降低体重调定点，节食后开放饮食体重会迅速反弹。而利拉鲁肽能显著降低DIO大鼠体重和体重调定点。这种药物对体重的“后遗效应”不能用药物的直接作用解释。因此，我们推测除神经调节和体液调节外，GLP-1还可能通过免疫调节影响大鼠的能量代谢平衡,并且推测下丘脑小胶质细胞在其中扮演重要的角色。为验证我们的推测，我们选取DIO大鼠为肥胖动物模型，分别用GLP-1类似物、节食处理,分别观察处理期和停药期体重、体重调定点、下丘脑炎症等指标。同时建立原代培养的大鼠下丘脑小胶质细胞作为体外细胞模型,探讨GLP-1、小胶质细胞、下丘脑炎症及体重调定点间的关系。以神经-免疫调节的角度探讨GLP-1降低体重调定点的机制。

目前肥胖症的治疗存在体重反弹的难题。而新近出现的GLP-1类似物利拉鲁肽治疗肥胖具有减重效果好，减重后体重稳定的特点。前期研究中我们发现限制饮食可显著降低饮食诱导肥胖（DIO）大鼠体重，但不能降低体重调定点，开放饮食体重会迅速反弹。而利拉鲁肽能显著降低DIO大鼠体重和体重调定点，停药后体重保持较长时期稳定。我们推测GLP-1类似物可能通过免疫调节影响大鼠的能量代谢平衡。并且推测下丘脑小胶质细胞在免疫调节中扮演重要的角色。为验证我们的推测，我们选取DIO大鼠为肥胖动物模型，分别应用GLP-1类似物利拉鲁肽、节食进行处理。并分别观察处理期和停药期体重、体重调定点、下丘脑炎症等相关指标。探讨GLP-1类似物处理与下丘脑炎症之间的关系，从而以神经-免疫调节的角度探讨GLP-1降低机体体重调定点的机制。在课题负责人刘红教授的领导下，经历四年艰苦而富有成效的研究，本课题组克服具体研究中动物实验分组多，实验设计复杂；提取小胶质细胞等诸多技术非难题。证实了GLP-1能够通过对肥胖下丘脑小胶质细胞的神经免疫反应抑制而降低体重调定点。在细胞模型中通过GLP-1通过抑制toll样受体4（TLR4）/MyD88/ TRAF6/NF-κB/p65信号通路抑制小胶质细胞炎症反应和炎症因子释放。通过抑制Notch/Hes-1/CYLD信号通路，抑制小胶质细胞M1促炎表型，促进M2抑炎表型，从而抑制下丘脑炎症修复。本研究将为临床GLP-1类似物用于肥胖症治疗的优势提供基础研究依据，更为将来研发针对下丘脑炎症特异性靶点的减重药物提供思路。