下丘脑PVN-ARC-LHA Nesfatin-1通路构成、调控及在糖尿病胃动力障碍中的作用研究

Gastroparesis is a common complication of diabetes mellitus, and the pathogenesis is much more complex. It was less known for the central mechanism. Nesfatin-1 is a novel satiation peptide which not only inhibited foodintake and gastrointestinal motility, but also reduced weight. In the hypothalamus, nesfatin-l mainly distributed in the centers associated with feeding, such as the paraventricular nucleus (PVN), arcuate nucleus (ARC) and the hypothalamic lateral area (LHA). Our research showed that nesfatin-l neurons of the hypothalamus sent their fibers to next nucleus and constituted a network in the core group of the hypothalamus. Moreover, the nesfatin-l neurons mutually regulated the information coming from the stomach with other feeding-related factors. The hippocampus, an emotions and memory center, was also involved in gastric motility and feeding regulation here. This topic is intended to explore the construct of the hypothalamus PVN-ARC-LHA nesfatin-l neural/functional pathways, the roles in the regulation of food intake and gastric motility, and the interacted effects between other feeding-related factors. We would like to clarify the relationship between hypothalamus PVN-ARC-LHA nesfatin-l pathway and the pathological process of diabetic gastric motility disorders, to raise that the pathway of hypothalamus-hippocampus 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 diabetes or obesity.

胃轻瘫是糖尿病常见并发症，发病机制复杂，且中枢发病机制研究甚少。Nesfatin-l是新发现一种饱食性肽，其不仅能抑制摄食和胃肠运动，也可降低体重。在下丘脑Nesfatin-l主要分布于与摄食相关中枢，如室旁核（PVN），弓状核（ARC）和下丘脑外侧区（LHA）。我们研究发现，下丘脑Nesfatin-l神经元发出纤维不仅在下丘脑内核团间构成网络联系、与其它摄食相关因子相互影响调控胃的传入信息，而且与情绪和记忆相关的海马也相互关联，参与胃动力和摄食调控。本课题意皆探讨下丘脑PVN-ARC-LHA Nesfatin-l神经/功能通路构成，研究该通路在调控摄食和胃运动中的作用，观察其它摄食调节因子对该通路信息传递的交互影响，阐明该通路与糖尿病胃动力降低病理关系，提出下丘脑-海马通路可能也是中枢能量平衡调控的重要通路。目的是补充和完善能量平衡调控理论，为糖尿病、肥胖等防治提供新的策略和靶点。

胃动力障碍是糖尿病常见并发症，发病机制复杂。Nesfatin-l是新发现一种饱食性肽，在中枢主要分布于下丘脑，其不仅能抑制胃肠运动，也可降低体重，是连接机体内分泌和能量平衡的重要活性肽。本课题焦点是探讨海马-下丘脑（PVN-ARC-LHA）Nesfatin-l神经/功能通路在调控胃运动的作用和地位，及与糖尿病胃动力障碍病理关系，目的是补充和完善能量平衡调控理论，为糖尿病胃动力障碍防治提供新的策略和靶点。. 研究首次发现，下丘脑Nesfatin-1神经元发出纤维不仅在下丘脑核团间（PVN-ARC-LHA）构成网络联系，而且与边缘系统的海马、杏仁核或伏隔核也相互联接构成Nesfatin-1神经通路，并介导对下丘脑胃传入信息的调控，形成下丘脑-海马、杏仁核或伏隔核Nesfatin-1功能通路，该通路可上传胃肠反馈信息，下控胃肠运动和摄食功能。首次发现，海马、杏仁核或伏隔核可接受来自胃的传入信息，并接受来自下丘脑摄食相关中枢信息调控，其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。下丘脑在胃动力调控中占有重要地位，海马、杏仁核或伏隔核调控胃肠功能有赖于下丘脑共同完成。研究首次发现，糖尿病大鼠下丘脑、海马及胃粘膜Nesfatin-1表达显著降低，下丘脑-海马、以及下脑核团间Nesfatin-1神经元投射也显著减少，海马-下丘脑Nesfatin-1通路对胃传入信息以及胃运动调控显著减弱，Nesfatin-1并参与糖尿病大鼠摄食和饮水调控，提示该通路的靶点调控可为糖尿病、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。首次报道，在下丘脑Nesfatin-1与其它摄食影响因子（如MCH，α-MSH，Ghrelin，Motilin）在胃肠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，为促胃肠动力药物的开发以及糖尿病胃轻瘫的预防和治疗提供有价值的实验依据。. 研究成果在国际SCI期刊发表论文15篇，国内核心期刊发表论文9篇，并在国际会议上交流，得到同行专家的关注和认可。该研究不仅为脑肠肽的基础研究奠定了基础，还为临床上糖尿病胃轻瘫治疗提供了实验依据。本项目培养2位博士研究生和11位硕士研究生。