伏隔核-下丘脑-杏仁核 Orexin通路调控及对胃动力和摄食影响机制研究

The obese people are rapidly increasing in our country. Obesity is easy to induce a variety of complications (such as diabetes, cardiovascular disease, high cholesterol) and accelerated aging and death. Orexin is a brain gut peptide which could promote feeding, gastrointestinal motility and participate in the regulation of the positive energy metabolism. Orexin neurons in hypothalamus may send their fibers not only to constitute of a network connection within the hypothalamus, the study also found that, but also to connect with 'hedonic feeding center' nucleus accumbens or 'emotional' relevant central amygdala each other, and to participate in the gastric motility and the regulation of food intake. More and more studies have shown that it is closely related to the energy balance between the emotional related central (such as the amygdala, the nucleus accumbens) and feeding related central (such as hypothalamus) co-activation. This topic is to explore the formation of orexin pathway among the nucleus accumbens, hypothalamus and amygdala, the roles of this orexin pathway in the regulation of food intake and gastric motility, as well as other factors which were regulated with food intake on interaction of the channel of information transmission. And we would like to clarify the relationship between nucleus accumbens-hypothalamus-amygdala Orexin pathway and the pathological process of obesity food intake and gastric motility disorders, to raise that the pathway of nucleus accumbens-hypothalamus-amygdala is an important pathway for the regulation of energy balance in order to supplement and improve the theory of energy balance regulation and provide new strategies and targets for prevention and treatment of obesity.

肥胖人口在我国迅速递增，其易引起多种并发症（如糖尿病、心脑血管疾病、高血脂等），加速衰老和死亡。食欲素（Orexin）是脑肠肽，其主要功能是促进摄食、胃肠动力、参与能量平衡调控。Orexin神经元不仅在下丘脑内部核团间构成网络联系，本研究还发现，下丘脑Orexin神经元与'享乐摄食中枢'-伏隔核和'情绪'相关中枢-杏仁核也相互连接，并参与胃动力和摄食调控。越来越多研究显示，能量平衡维持与情绪相关中枢（如杏仁核、伏隔核、隔核等）和摄食调控中枢（如下丘脑）的共激活密切相关，并引起学者们的关注。本课题意皆探讨伏隔核-下丘脑-杏仁核Orexin神经/功能通路构成、该通路在调控胃运动和摄食中的作用，以及与该通路上其它摄食调节因子对该通路信息传递的交互影响，阐明该通路与肥胖病理关系，提出该通路是中枢能量平衡调控的重要通路之一，目的是补充和完善能量平衡调控理论，为肥胖、糖尿病等的防治提供新的策略。

肥胖易引起多种并发症（如糖尿病、心脑血管疾病、高血脂等），加速衰老和死亡。脑肠肽食欲素（Orexin）主要促进摄食、胃肠动力、参与能量平衡调控。本课题焦点是探讨伏隔核-下丘脑（LHA-Arc-PVN）-杏仁核Orexin神经/功能通路在调控胃动力和摄食中的作用，以及与该通路上其它摄食调节因子对信息传递的交互影响，阐明该通路与肥胖病理关系，提出该通路是中枢能量平衡调控的重要通路之一，目的是补充和完善能量平衡调控理论，为肥胖、糖尿病等防治提供新的策略。.研究发现，下丘脑Orexin-A/OX-1R神经元发出纤维不仅在下丘脑核团间（LHA-Arc-PVN）构成网络联系，而且与‘享乐摄食中枢’伏隔核和‘情绪’相关中枢杏仁核也相互联接构成Orexin-A/OX-1R神经通路，并介导对下丘脑胃传入信息、摄食和胃功能调控，形成下丘脑-杏仁核/伏隔核Orexin-A功能通路。该通路可上传胃肠反馈信息，下控胃动力、胃酸分泌及摄食。杏仁核和伏隔核不仅接受来自胃的传入信息，也接受来自下丘脑摄食相关中枢调控，且也可发出信息反馈至下丘脑，‘应答’下丘脑对胃传入信息的调控。下丘脑Orexin在胃动力和摄食调控中占有重要地位，杏仁核和伏隔核在调控摄食/胃动力中有赖于下丘脑共同完成。研究发现，肥胖和肥胖抵抗大鼠下丘脑、杏仁核Orexin-A/OX-1R表达显著增加，下丘脑-杏仁核/伏隔核以及下脑核团间Orexin-A/XO-1R神经元投射也显著增加，尤以肥胖抵抗大鼠最为显著；同时发现，肥胖和肥胖抵抗大鼠下丘脑Orexin通路对胃传入信息、摄食及胃运动调控显著增强，且Orexin-A参与肥胖大鼠能量代谢和自发活动调控。该通路的靶点调控可为肥胖等能量代谢相关疾病的防治提供新的策略和实验依据。研究发现，在下丘脑Orexin-A与其它摄食影响因子（如MCH，大麻素，NPY，Ghrelin，Nesfatin-1，甘丙肽）在摄食和胃功能调控中相辅相成、相互影响、协同/共同维持机体能量平衡。本研究为抗肥胖药物的开发及预治提供有价值的实验依据。.研究成果在国际SCI期刊发表论著16篇，北大核心期刊发表论著4篇，并在国际会议上交流，得到同行专家的关注和认可。本项目培养5位博士研究生和20位硕士研究生。