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

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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.