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

目的：研究葡萄糖、胰岛素、瘦素和胃饥饿素等内脏来源的重要摄食控制物质对下丘脑摄食调节中枢神经元的影响，包括神经肽Y （NPY）、促黑素原（POMC）和食欲素神经元。方法：从6-8周龄大鼠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。另外，采用体内饲养实验和组织学方法。降低葡萄糖浓度可激活下丘脑外侧的促食素神经元，这提供了一种调节促食素神经元的机制。除了摄食作用外，我们还发现食欲素激活腹侧被盖区的多巴胺神经元，从而刺激过度运动和刻板印象等情绪行为。弓形核（ARC）中的NPY神经元与摄食刺激有关，通过降低葡萄糖浓度、食欲素和胃饥饿素激活，而升高葡萄糖浓度、瘦素和胰岛素抑制NPY神经元。ARC的POMC神经元和下丘脑腹内侧（VMH）的葡萄糖反应神经元都与进食抑制有关，升高葡萄糖浓度、瘦素和胰岛素会激活它们，而降低葡萄糖浓度和食欲素会抑制它们。食欲素1型和2型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神经元的抑制耦合。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，因此是整合中心。

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.