白色脂肪棕色化在GLP-1受体激动剂减重中的作用和机制研究

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.

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。

围绕着肥胖、非酒精性脂肪肝的发病机制和GLP-1受体激动剂干预的研究方向，本研究使用多种与脂代谢密切相关的基因敲除小鼠模型和肥胖、2型糖尿病常规的体内、外模型，结合申请人熟悉的分子生物学和细胞生物学技术，探讨降糖药物肠促胰素相关制剂GLP-1受体激动剂（GLP-1 RA）在与糖脂代谢密切相关的周围靶组织器官包括肝脏、脂肪和骨骼肌的作用和相关机制。主要研究结果发现了GLP-1受体激动剂的作用新靶点及新机制：（1）在高脂饮食诱导的肥胖小鼠模型中发现了GLP-1 RA exenatide调控脂毒性导致肝脏内质网应激的分子机制，提示SIRT1/HSF1/HSP通路参与GLP-1 RA改善脂肪肝相关的内质网应激，并在棕榈酸诱导人肝癌细胞及小鼠原代肝细胞脂质沉积的模型上得到证实。该研究证实了GLP-1 RA可显著改善高脂饮食诱导的肝脏内质网应激和脂肪沉积，并首次发现这一作用是由SIRT1介导的。（2）对脂肪组织的研究还发现GLP-1 RA可改善高脂饮食诱导肥胖模型脂肪组织炎症和缺氧状态，这一作用与GLP-1 RA改善脂肪组织血管微循环的重构有关。（3）短期腹腔注射GLP-1 RA exenatide可减轻ob/ob肥胖小鼠骨骼肌的脂质沉积，其机制可能与促进脂质分解和抑制脂质合成有关，并且不依赖于体重的下降，这更新了目前对GLP-1 RA改善脂质异常沉积的作用主要依赖于减重的认识；该作用机制可能与骨骼肌AMPK通路的激活、胰岛素敏感性改善及脂质代谢改善有关，提示骨骼肌脂质合成及代谢是GLP-1 RA的作用靶点。（4）阐明了GLP-1 RA改善肥胖2型糖尿病小鼠肾脏损伤的作用之一是通过调控SIRT1/TXNIP通路减轻了肾脏肾小球系膜细胞的凋亡，为临床上使用GLP-1受体激动剂治疗2型糖尿病早期肾损伤提供了新的机制。上述研究结果更新了对GLP-1 RA作用靶点及机制的认识，为其在临床中的应用提供了新的理论依据。