Cai X J, Evans M L, Lister C A, Leslie R A, Arch J R, Wilson S, Williams G
Diabetes and Endocrinology Research Group, University of Liverpool, UK.
Diabetes. 2001 Jan;50(1):105-12. doi: 10.2337/diabetes.50.1.105.
Orexins are novel appetite-stimulating peptides expressed in the lateral hypothalamic area (LHA), and their expression is stimulated by hypoglycemia in fasted rats. We investigated activation of orexin and other neurons during insulin-induced hypoglycemia using the immediate early gene product Fos. Insulin (50 U/kg) lowered plasma glucose by >50% after 5 h and stimulated feeding sixfold compared with saline-injected controls. Hypoglycemic rats allowed to feed and normoglycemic controls both showed sparse Fos-positive (Fos+) neurons in the LHA and the paraventricular nucleus (PVN) and arcuate nucleus (ARC) and showed none in the nucleus of the solitary tract (NTS), which relays visceral feeding signals to the LHA. In the LHA, total numbers of Fos+ neurons were comparable in fed hypoglycemic and control groups (60 +/- 6 vs. 52 +/- 4 cells/mm2, P > 0.05), as were Fos+ neurons immunoreactive for orexin (1.4 +/- 0.4 vs. 0.6 +/- 0.4 cells/mm2, P > 0.05). By contrast, hypoglycemic rats that were fasted showed significantly more Fos+ nuclei in the LHA (96 +/- 10 cells/mm2, P < 0.05, vs. both other groups) and Fos+ orexin neurons (8.4 +/- 3.3 cells/mm2, P < 0.001, vs. both other groups). They also showed two- to threefold more Fos+ nuclei (P < 0.001) in the PVN and ARC than both fed hypoglycemic rats and controls and showed strikingly abundant Fos+ neurons in the NTS and dorsal motor nucleus of the vagus. In parallel studies, whole hypothalamic orexin-A levels were not changed in hypoglycemic rats, whether fasted or freely fed, whereas orexin-B levels were 10-fold higher in hypoglycemic fasted rats than in control and hypoglycemic fed groups. These data support our hypothesis that orexin neurons are stimulated by falling glucose levels but are readily inhibited by signals related to nutrient ingestion and suggest that they may functionally link with neuronal activity in the NTS. Orexin-A and -B may play specific roles in behavioral or neuroendocrine responses to hypoglycemia.
食欲肽是在下丘脑外侧区（LHA）表达的新型促食欲肽，在禁食大鼠中，低血糖可刺激其表达。我们使用即刻早期基因产物Fos研究了胰岛素诱导的低血糖期间食欲肽及其他神经元的激活情况。胰岛素（50 U/kg）在5小时后使血浆葡萄糖降低>50%，与注射生理盐水的对照组相比，进食量增加了六倍。允许进食的低血糖大鼠和血糖正常的对照组在LHA、室旁核（PVN）、弓状核（ARC）中Fos阳性（Fos+）神经元均较少，而在将内脏进食信号传递至LHA的孤束核（NTS）中则无Fos+神经元。在LHA中，进食的低血糖大鼠组和对照组的Fos+神经元总数相当（分别为60±6个/mm²和52±4个/mm²，P>0.05），对食欲肽免疫反应阳性的Fos+神经元数量也相当（分别为1.4±0.4个/mm²和0.6±0.4个/mm²，P>0.05）。相比之下，禁食的低血糖大鼠LHA中的Fos+核显著增多（96±10个/mm²，P<0.05，与其他两组相比），Fos+食欲肽神经元也增多（8.4±3.3个/mm²，P<0.001，与其他两组相比）。它们PVN和ARC中的Fos+核也比进食的低血糖大鼠和对照组多两到三倍，并且在NTS和迷走神经背运动核中Fos+神经元明显丰富。在平行研究中，无论是禁食还是自由进食的低血糖大鼠，下丘脑整体食欲肽A水平均未改变，而禁食的低血糖大鼠中食欲肽B水平比对照组和进食的低血糖大鼠组高10倍。这些数据支持了我们的假设，即血糖水平下降会刺激食欲肽神经元，但与营养物质摄入相关的信号会轻易抑制它们，并表明它们可能在功能上与NTS中的神经元活动相关联。食欲肽A和B可能在对低血糖的行为或神经内分泌反应中发挥特定作用。
