Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats
Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats
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DOI：
10.1016/s0006-8993(98)00985-8
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发表时间：
1999-01-16
期刊：
影响因子：
2.9
通讯作者：
Kalra, SP
中科院分区：
文献类型：
--
作者：
Dube, MG;Xu, B;Kalra, SP
放置在大鼠下丘脑腹内侧（VMH）的电解质损伤诱导即时暴食和过度体重增加。由于神经肽Y（NPY）是一种有效的下丘脑食欲信号，脂肪细胞分泌的瘦素调节NPY的输出，我们测试的假设，改变NPY-瘦素信号可能是VMH损伤的大鼠摄食过多的基础。VMH损伤的大鼠在手术后第2、7和21天以与时间相关的方式处死，以避免过度进食和体重过度增加。出乎意料的是，NPY浓度下丘脑室旁核（PVN），一个主要的网站的NPY释放刺激的喂养，并在其他网站，如背内侧核，下丘脑外侧区和正中隆起弓状核减少，最早的减少发生在第2天的PVN。VMH损伤大鼠PVN的基础和KF诱发的NPY释放量明显低于对照组。下丘脑NPY基因表达的分析表明，虽然每天减少在0800至2200小时发生在对照组大鼠，NPY mRNA浓度显着降低，在这些时间在VMH-损伤大鼠下丘脑。脂肪细胞中瘦素的合成，瘦素mRNA水平也显着改变VMH损伤大鼠。在对照组中观察到的2200 h脂肪细胞瘦素mRNA从0800 h开始的每日增加模式被消除，2200 h的较高水平的瘦素基因表达在0800 h保持。VMH损伤大鼠血清瘦素和胰岛素水平的增加模式不同。血清胰岛素浓度增加到最大的第2天，并保持在该水平的第21天病变后，另一方面，血清瘦素水平在此期间缓慢增加，在一个时间相关的方式。这些结果表明，VMH损伤大鼠的摄食量和体重过度增加与下丘脑NPY的总体减少和下丘脑瘦素信号的增强有关。血清瘦素和胰岛素水平增加的不同时间过程表明，独立的机制负责其增强分泌，这些激素也不VMH病变改变了NPY基因表达的每日节律。这些观察结果强调存在一个独立的机制控制下丘脑NPY基因表达的每日节律，并建议瘦素反馈作用需要一个完整的VMH。(C)1999 Elsevier Science B.V，保留所有权利。
Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibitings hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and Kf-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH. (C) 1999 Elsevier Science B.V, All rights reserved.