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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：本研究旨在探讨内脏源性重要摄食控制物质葡萄糖、胰岛素、瘦素和ghrelin对下丘脑摄食调节中枢神经元神经肽Y（neuropeptide Y，NPY）、阿黑皮素原（proopiomelanocortin，POMC）和食欲素（orexin）的影响。通过测量胞浆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，然后通过免疫细胞化学鉴定神经元的种类。结果：1.降低葡萄糖浓度可激活下丘脑外侧区食欲素神经元，为食欲素神经元的调节提供了机制。除摄食作用外，我们还发现食欲素还能激活腹侧被盖区的多巴胺神经元，从而刺激情绪行为，如过度运动和刻板行为。2.弓状核（ARC）中与摄食刺激有关的NPY神经元被葡萄糖浓度降低、食欲素和ghrelin激活，而葡萄糖浓度升高则抑制它们。3. ARC中的POMC神经元和腹内侧下丘脑（VMH）中的葡萄糖反应神经元，两者都涉及摄食抑制，通过升高葡萄糖浓度、瘦素和胰岛素而被激活，而降低葡萄糖浓度和食欲素则可抑制食欲素1型和2型受体与不同的信号转导有关5. ARC中的NPY神经元和POMC神经元是影响摄食的主要内脏和神经物质的直接靶点，从而充当整合中心。