Regulation by glucose and insulin of the neurons in feeding-regulatory centers and its alteration in obesity and diabetes

葡萄糖和胰岛素对摄食调节中心神经元的调节及其在肥胖和糖尿病中的改变

基本信息

批准号：
12470231
负责人：
YADA Toshihiko
金额：
$ 8.45万
依托单位：
Jichi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

AIM : This study aimed to clarify the effects of important feeding-controlling substances of the visceral origin, such as glucose, insulin, leptin and ghrelin, on the neurons in the hypothalamic feeding-regulatory centers, which include neuropeptide Y (NPY), proopiomelanocortin (POMC) and orexin neurons.METHODS : Single neurons were isolated from the hypothalamus of rats aged 6-8 weeks. The responses of the single neurons to substances were assessed by measurements of cytosolic Ca^<2+> concentration and ion channel currents, followed by immunocytochemical identification of the neuron species. In addition, in vivo feeding experiments and histological methods were used.RESULTS:1.Orexin neurons in the lateral hypothalamus were activated by lowering glucose concentrations, providing a mechanism how orexin neurons are regulated. In addition to its feeding effect, we found that orexin activates dopamine neurons in the ventral tegmental area and thereby stimulates emotional behavior such as hyperlocomotion and stereotypy.2.NPY neurons in the arcuate nucleus (ARC), which are implicated in stimulation of feeding, were activated by lowering glucose concentrations, orexin and ghrelin, while they were inhibited by elevating glucose concentrations, leptin and insulin.3.POMC neurons in the ARC and glucose-responsive neurons in the ventromedial hypothalamus (VMH), both implicated in inhibition of feeding, were activated by elevating glucose concentrations, leptin and insulin, while they were inhibited by lowering glucose concentrations and orexin.4.Orexin type 1 and 2 receptors were linked to distinct signal transduction mechanisms and coupled to activation of NPY neurons and inhibition of POMC neurons, respectively.5.NPY neurons and POMC neurons in the ARC are the direct targets of principal visceral and neural substances that affect feeding and thereby serve as the integration centers.

目的：本研究旨在阐明内脏来源的重要摄食控制物质，如葡萄糖、胰岛素、瘦素和生长素释放肽，对下丘脑摄食调节中心神经元的影响，其中包括神经肽 Y (NPY)、阿黑皮素原(POMC)和食欲素神经元。方法：从6-8周龄大鼠的下丘脑分离单个神经元。通过测量胞质Ca 2+ 浓度和离子通道电流来评估单个神经元对物质的反应，然后对神经元种类进行免疫细胞化学鉴定。此外，还采用了体内喂养实验和组织学方法。结果：1.降低葡萄糖浓度可以激活下丘脑外侧的食欲素神经元，提供了调节食欲素神经元的机制。除了其摄食作用外，我们发现食欲素激活腹侧被盖区的多巴胺神经元，从而刺激情绪行为，如过度运动和刻板印象。2.弓状核（ARC）中的NPY神经元，与刺激摄食有关，降低葡萄糖浓度、食欲素和生长素释放肽可以激活这些神经元，而升高葡萄糖浓度、瘦素和胰岛素则可以抑制这些神经元。 3. ARC 和 ARC 中的 POMC 神经元下丘脑腹内侧 (VMH) 中的葡萄糖反应神经元均与摄食抑制有关，通过升高葡萄糖浓度、瘦素和胰岛素来激活，而通过降低葡萄糖浓度和食欲素来抑制它们。 4. 1 型和 2 型食欲素受体与不同的信号转导机制有关，并分别与 NPY 神经元的激活和 POMC 神经元的抑制有关。 5. ARC 中的 NPY 神经元和 POMC 神经元是影响进食的主要内脏和神经物质，从而充当整合中心。