Dube M G, Xu B, Kalra P S, Sninsky C A, Kalra S P
Department of Physiology, POB 100274, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Brain Res. 1999 Jan 16;816(1):38-46. doi: 10.1016/s0006-8993(98)00985-8.
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 exhibiting 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 K+-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.
在大鼠腹内侧下丘脑（VMH）植入电解损伤会导致即刻食欲亢进和体重过度增加。由于神经肽Y（NPY）是一种强大的下丘脑促食欲信号，且脂肪细胞分泌的瘦素调节NPY的输出，我们检验了以下假设：NPY能-瘦素信号改变可能是VMH损伤大鼠食欲亢进的基础。在术后第2天、第7天和第21天，处死以时间相关方式表现出食欲亢进和体重过度增加的VMH损伤大鼠。非常出乎意料的是，下丘脑室旁核（PVN）（NPY释放以刺激进食的主要部位）以及其他部位，如背内侧核、下丘脑外侧区和正中隆起-弓状核中的NPY浓度降低，最早的降低仅在术后第2天出现在PVN中。VMH损伤大鼠PVN的体外基础NPY释放和K⁺诱发的NPY释放显著低于对照组。下丘脑NPY基因表达分析表明，虽然VMH损伤大鼠下丘脑在08:00至22:00期间NPY mRNA的每日降低情况与对照大鼠相同，但在这些时间点其NPY mRNA浓度明显降低。VMH损伤大鼠脂肪细胞中的瘦素合成（以瘦素mRNA水平表示）也发生了深刻改变。对照组中观察到的脂肪细胞瘦素mRNA在22:00时从08:00开始的每日增加模式被消除，22:00时较高的瘦素基因表达水平在08:00时得以维持。VMH损伤大鼠血清瘦素和胰岛素水平的增加模式不同。血清胰岛素浓度在术后第2天增加到最大值，并在损伤后第21天保持在该水平；另一方面，在此期间血清瘦素水平以时间相关方式缓慢增加。这些结果表明，VMH损伤大鼠的食欲亢进和体重过度增加与下丘脑NPY的总体减少以及瘦素向下丘脑的信号增强有关。血清瘦素和胰岛素水平增加的不同时间进程表明它们分泌增加的机制独立，并且这些激素和VMH损伤均未改变NPY基因表达的每日节律。这些观察结果强调了存在一种独立机制控制下丘脑NPY基因表达的每日节律，并表明瘦素反馈作用需要完整的VMH。
