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

目的：探讨内脏来源的重要摄食调控物质葡萄糖、胰岛素、瘦素和Ghrelin对神经肽Y(NPY)、前阿片黑素皮质素(POMC)和增食欲素神经元等下丘脑摄食调节中枢神经元的影响。通过细胞内钙离子浓度和离子通道电流的测定以及神经元种类的免疫细胞化学鉴定来评估单个神经元对物质的反应。结果：1.通过降低葡萄糖浓度激活下丘脑外侧区Oresin神经元，为Oresin神经元的调控提供了机制。2.与摄食刺激有关的弓状核(ARC)中的NPY神经元通过降低葡萄糖浓度、增食欲素和Ghrelin而被激活，而通过升高葡萄糖浓度、瘦素和胰岛素来抑制它们。3.弓状核(ARC)中的POMC神经元和下丘脑腹内侧部(VMH)中与摄食抑制有关的葡萄糖反应神经元通过升高葡萄糖浓度、瘦素和胰岛素而被激活。Orexin1和2型受体分别与不同的信号转导机制相连，并分别与NPY神经元的激活和POMC神经元的抑制相耦合。5.ARC内的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，因此是整合中枢。

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.