中枢神经系统MC4R神经元介导Amylin促进背肩胛棕色脂肪产热的研究

以脂肪沉积为特征的肥胖已成为健康难题，胰淀素(Amylin)通过黑素皮质素4型受体(MC4R)抑食和促进背肩胛棕色脂肪(IBAT)产热，有效地降低了肥胖的发生。然而，中枢MC4R神经元作用尚不明确。因此，本研究假设中枢神经存在表达MC4R神经元的主效区域，介导Amylin促进IBAT产热。. 为此，利用LoxTB MC4R小鼠因MC4R失活导致肥胖、又可局部再激活的特点和Amylin引发IBAT温度升高的现象，通过双边注射腺病毒载体AAV-Cre-GFP，再激活弓状核、室旁核、背外侧被盖核和孤束核等区域MC4R作用，辅以IBAT去神经支配和伪狂犬病毒逆行追踪，结合脑室注射MC4R激动或拮抗剂再腹腔注射Amylin，获得IBAT温度、神经元共表达、基因、蛋白、谷氨酸、氨基丁酸、葡萄糖和胰岛素数据。. 借此，寻找Amylin通过中枢神经MC4R调控IBAT产热关键核团，从而为减缓肥胖提供靶点。

Accumulation of adipose tissue associating with obesity is currently one of the main public health concerns. Based on amylin-induced suppression of feeding and stimulation of thermogenesis in interscapular brown adipose tissue (IBAT) require activation of MC4R signaling. Thermogenesis is a therapeutic interest to treat excess fat deposition. However, the pathway that govern these processes are not fully understood, we thus hypothesis that there is multi-subsets of MC4R neurons in central nervous system (CNS) contribute of regulation of thermogenesis. . We will apply LoxTB MC4R mice to investigate the physiological function of MC4R signaling based on their obesity and Cre-dependent reactivation, also amylin-induced stimulation of thermogenesis. AAV-Cre-GFP will be injected into the skull via bilaterally at defined positions (Arcuate nucleus, ARC, Laterodorsal tegmental nucleus, LDT and Nucleus of the solitary tract, NTS, etc) and reappear the role of MC4R. Then IBAT intercostal sympathetic nerve will be denervated and the pathway between CNS and IBAT was confirmed by pseudorabies virus (PRV) for the transsynaptic retrograde, and the mice received intracerebroventricular injection with antagonists and agonists of MC4R, then intraperitoneal injected amylin, with a specific focus on IBAT temperature, exploring the co-expression neurons, as well as the expression of relating gene and protein, the concentration of glutamate and GABA, also the glucose and insulin from the serum.. Together, we hope the results identify the areas in CNS where control the amylin-induced stimulation of thermogenesis of IBAT. Then facilitate understanding the target of thermogenesis for amylin-based combinations with MC4R, and that may be a novel therapeutic approach for obesity.