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。

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.