We believe that the results of this study provide useful insights into the mechanisms responsible for the short-term regulation of food intake. In the immunohistochemical experiment, the rats were not provided access to food in order to eliminate the effect of feeding on the activity of ORX-A and MCH neurons. Then in the immunohistochemical experiment, we examined the c-Fos expression in the ORX-A and MCH neurons in the PF/LH and c-Fos expression in the Arc at a specific timing, corresponding to 2 h after the rats started eating in the behavioral study, because the peak c-Fos expression reportedly occurs 1.5–2 h after stimulation. First, we determined the time course of the feeding behavior during the 2DG-induced glucoprivation and insulin-induced hypoglycemia. In the behavioral experiment, we examined the plasma glucose level and body temperature as indices of metabolic status, and also examined food intake response. The present study included a behavioral experiment and a separate immunohistochemical experiment in the same rats. We also examined the c-Fos expression in the arcuate nucleus (Arc), because neuropeptide Y (NPY) neurons reportedly have projections to ORX-A and MCH neurons and are glucosensitive. In the present study, in order to elucidate the involvement of ORX-A and MCH neurons in the short-term regulation of food intake, we examined the food intake response and the c-Fos expression in MCH and ORX neurons in the PF/LH. Thus, it is still uncertain whether or not the MCH neurons are responsive to acutely reduced glucose availability and responsible for the short-term regulation of food intake. However, this study did not directly demonstrate the involvement of MCH neurons in the regulation of food intake induced by reduced glucose availability. Another study demonstrated that glucose infusion after fasting reduced the expression of the phosphorylated cAMP response element-binding protein, suggesting that MCH neurons might be involved in food intake behavior in response to fasting, and these neurons are responsive to the plasma glucose level. In contrast, it has been also reported that MCH neurons are possibly involved in the glucose sensing system, because hypothalamic MCH mRNA levels are increased by hypoglycemic stimulations such as fasting or treatment with insulin or 2DG. The results of several studies showed that MCH neurons are not responsive to reduced glucose availability. In contrast to ORX-A neurons, the knowledge available concerning the involvement of MCH neurons in the short-term regulation of food intake is limited and controversial. However, the involvement of ORX-A neurons in the short-term regulation of food intake has not been fully established, because most of the previous studies did not examine the time course of the plasma glucose concentration, the metabolic status, and the corresponding feeding behavior in addition to examining the activation of ORX-A neurons during glucoprivation or hypoglycemia. These results suggest that the ORX-A neurons are almost certainly responsive to acutely reduced glucose availability. ORX-A neurons are possibly glucosensitive and believed to be involved in the short-term regulation of food intake several studies, but not all, have demonstrated that reduced glucose availability induced by systemic and intracranial administration of 2-deoxy- d-glucose (2DG), or systemic insulin-induced hypoglycemia, stimulated c-Fos expression in the ORX-A neurons or orexin mRNA expression. Furthermore, some studies have shown that the ORX-A neurons interact morphologically with the MCH neurons. It is also known that the neurons expressing melanin-concentrating hormone (MCH) and orexin-A (ORX-A) are distributed at the perifornical and lateral hypothalamic areas (PF/LH) of the hypothalamus, and it is known that both of these peptides are orexigenic. It is well-established that glucosensitive neurons are located in the lateral hypothalamic area. The short-term regulation of ingestive behavior is mediated mainly by reduced glucose availability, or plasma glucose concentration, and glucosensitive neurons are involved in the short-term regulation of food intake.
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