Inhibition of hypothalamic neuropeptide Y gene expression by insulin.
Inhibition of hypothalamic neuropeptide Y gene expression by insulin.
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DOI：
10.1210/endo.130.6.1597158
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发表时间：
1992-06
期刊：
影响因子：
4.8
通讯作者：
M. Schwartz;A. Sipols;J. L. Marks;G. Sanacora;Jeffery D. White;A. Scheurink;S. Kahn;D. Baskin;S. Woods;D. Figlewicz
中科院分区：
文献类型：
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作者：
M. Schwartz;A. Sipols;J. L. Marks;G. Sanacora;Jeffery D. White;A. Scheurink;S. Kahn;D. Baskin;S. Woods;D. Figlewicz
胰岛素在大脑中起作用以抑制进食，而神经肽Y（NPY）则具有相反的作用。由于禁食会降低血浆胰岛素水平并增加下丘脑神经肽Y的合成，我们提出胰岛素可能抑制下丘脑神经肽Y基因的表达。为了验证这一假设，我们使用放射免疫分析（RIA）和原位杂交组织化学方法来确定在禁食期间中枢给予胰岛素是否能降低下丘脑特定区域中神经肽Y及其信使核糖核酸（mRNA）的水平。三组长 - 埃文斯大鼠进入一项72小时的研究方案。在此期间，一组大鼠自由进食，而其他组则禁食。进食的大鼠每隔12小时接受一次脑室内（icv）生理盐水载体注射，而禁食组则单独接受脑室内载体或同时接受胰岛素（4毫单位/12小时）。在仅用载体处理的大鼠中，禁食使弓状核中前原神经肽Y mRNA的表达显著增加至进食对照组的179 ± 20%。禁食期间给予脑室内胰岛素消除了这种增加（为进食对照组的99 ± 14%；与禁食且仅用载体处理的大鼠相比，P < 0.05）。禁食期间中枢给予胰岛素还使从室旁核（PVN）打孔获取的样本中神经肽Y免疫反应浓度（875 ± 122皮克/孔）降低至低于仅用载体处理的大鼠（1396 ± 435皮克/孔；P < 0.05），与自由进食对照组的值（814 ± 170皮克/孔）相似。相比之下，禁食和中枢给予胰岛素均未改变下丘脑其他四个区域（视上核、腹内侧核、背内侧核和弓状核）中神经肽Y的水平。在较低剂量（2毫单位/天）下连续脑室内输注胰岛素在Wistar大鼠较短时间（48小时）的食物剥夺期间产生了类似的结果。在这项研究中，中枢胰岛素输注还抑制了与禁食相关的弓状核前原神经肽Y mRNA水平的增加，并且不影响血浆葡萄糖或胰岛素水平。这表明胰岛素在局部起作用以抑制下丘脑神经肽Y mRNA的表达。我们得出结论，禁食期间室旁核中神经肽Y水平以及弓状核中前原神经肽Y mRNA水平的增加可被脑室内胰岛素抑制。因此，禁食通过一种依赖于低胰岛素水平的机制增加了下丘脑中沿弓状核 - 室旁核途径的神经肽Y生物合成。
Insulin acts in the brain to suppress feeding, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting lowers plasma insulin levels and increases hypothalamic synthesis of NPY, we proposed that insulin may inhibit hypothalamic NPY gene expression. To test this hypothesis, we used RIA and in situ hybridization histochemistry to determine if centrally administered insulin could reduce levels of both NPY and its messenger RNA (mRNA) in discreet hypothalamic regions during fasting. Three groups of Long-Evans rats were entered into a 72-h study protocol. One group was fed ad libitum during this period, while the others were fasted. Fed rats received intracerebroventricular (icv) injections of saline vehicle at 12-h intervals, whereas fasted groups received icv vehicle alone or with insulin (4 mU/12 h). In vehicle-only treated rats, fasting significantly increased expression of preproNPY mRNA in the arcuate nucleus to 179 +/- 20% of fed controls. Administration of icv insulin during fasting abolished this increase (99 +/- 14% of fed controls; P less than 0.05 vs. fasted, vehicle-treated rats). Central insulin administration during fasting also reduced immunoreactive NPY concentrations in samples punched from the paraventricular nucleus (PVN) (875 +/- 122 pg/punch) to levels below vehicle-only treated rats (1396 +/- 435 pg/punch; P less than 0.05), similar to free-feeding control values (814 +/- 170 pg/punch). By comparison, neither fasting nor central insulin administration altered NPY levels in four other hypothalamic regions (supraoptic, ventromedial, dorsomedial, and arcuate nuclei). Continuous icv insulin infusion at a lower dose (2 mU/day) produced a similar result during a shorter period (48 h) of food deprivation in Wistar rats. In this study, central insulin infusion also inhibited the fasting-related increase in arcuate preproNPY mRNA levels and did not affect plasma glucose or insulin levels. This suggests that insulin acts locally to inhibit hypothalamic NPY mRNA expression. We conclude that the increase of levels of NPY in the PVN and preproNPY mRNA in the arcuate nucleus during fasting are inhibited by icv insulin. Fasting, therefore, increases NPY biosynthesis along an arcuate nucleus-PVN pathway in the hypothalamus via a mechanism dependent on low insulin levels.