一半以上的2型糖尿病患者伴有肥胖。肥胖2型糖尿病的治疗一直是临床难题，传统治疗药物如胰岛素、磺脲类及噻唑烷二酮类均存在增加体重的风险，不能兼顾血糖与体重的双重控制。胰高血糖素样肽-1(GLP-1)受体激动剂作为一种新型降糖药物，在降血糖同时能有效降低体重、改善代谢紊乱并长期维持，但减重机制尚未完全阐明。之前认为GLP-1受体激动剂降低体重的作用主要与其抑制中枢食欲、延缓胃排空有关，但观察时间均较短。申请人前期研究发现，GLP-受体激动剂对饮食诱导的肥胖小鼠的减重作用在初期与摄食减少有关，之后可能与其作用于脂肪组织增加脂肪动员、促进白色脂肪棕色化有关，分子机制有待进一步阐明。本项目将结合申请人熟悉的脂肪细胞生物学和分子生物学技术，使用多种与脂肪代谢密切相关的基因敲除小鼠模型和2型糖尿病常规的体内、外模型，多层次探讨其中的具体机制，从而为临床观察到的现象及该药的临床使用提供新的理论依据。

Studies have indicated that over half of the type 2 diabetes patients are accompanied with obesity. It has been a clinical difficulty for the therapy of obesity- associated type 2 diabetes for a long time. Traditional drugs, such as insulin, sulfonylureas and thiazolidinediones, fail to benefit both from blood glucose and body weight due to their increased risks of weight gain. Glucagon-like peptide-1(GLP-1) receptor agonist, a novel antidiabetic drug, could obviously decrease the body weight and improve the metabolic disturbances besides its blood glucose lowering effect. However, the mechanisms for its effect on weight loss have not been clearly defined. Previous short-term studies showed that the weight lowering effect of GLP-1 receptor agonist is largely attributed to the inhibition of central appetite and delay of gastric emptying. Our previous study from diet-induced obese mouse model found that it was related to the reduced food intake at the beginning, but could be due to the increased mobilization and browning of white adipose tissues at the long-term stage. The molecular mechanisms of these remain to be elucidated. For this purpose, we will use techniques in molecular and cell biology of adipocytes, and several experimental models including gene knock-out mouse models and in vivo and in vitro models of type 2 diabetes, to investigate this program in many levels. It will provide new theoretical basis for the clinical observations and the use of GLP-1 receptor agonist.