Kalra P S, Dube M G, Xu B, Farmerie W G, Kalra S P
Department of Physiology, University of Florida College of Medicine, Gainesville 32610-0274, USA.
J Neuroendocrinol. 1998 Jan;10(1):43-9. doi: 10.1046/j.1365-2826.1998.00170.x.
Microinjection of colchicine (COL), a neurotoxin that blocks axoplasmic flow in the neurons, bilaterally into the ventromedial nucleus (VMN) evokes transient hyperphagia and body weight gain. These shifts in energy balance occurred in conjunction with development of increased sensitivity to neuropeptide Y (NPY), the endogenous orexigenic signal. In order to trace the aetiology of NPY supersensitivity, we have evaluated (1) NPY Y1 and Y5 receptor (R) gene expression in the hypothalamus and (2) the possibility of alterations in the inhibitory action of leptin, a hormone produced by lipocytes. Adult male rats were rendered hyperphagic with bilateral microinjections of COL (4 microg/side) into the VMN. We observed that hypothalamic NPY Y1 mRNA levels, as measured by RNAase protection assay, were significantly increased on day 2 and returned to the control level on day 4 in COL-injected rats. The effects on NPY Y5R mRNA were not as clear cut. Interestingly, serum leptin levels increased in association with the hyperphagia and body weight gain, thereby raising the likelihood of development of resistance to the suppressive effect of endogenous leptin on food intake. Indeed, intracerebroventricular injection of 7 microg human recombinant leptin, a dose that attenuated daily food intake in normal and fasted rats, was completely ineffective in attenuating hyperphagia in COL-treated rats. These results show that transient hyperphagia induced by interruption of signalling in the VMN may be caused by increased sensitivity to NPY, which may be caused, in part, by increased expression of NPY Y1R in hypothalamic sites involved in regulation of ingestive behaviour. Additionally, the observation of increased leptin release and concurrent development of leptin resistance suggest that a normally functioning VMN may be necessary for the central inhibitory effects of leptin on food intake.
向双侧腹内侧核（VMN）微量注射秋水仙碱（COL）（一种可阻断神经元轴浆运输的神经毒素）会引发短暂的食欲亢进和体重增加。这些能量平衡的变化与对内源性促食欲信号神经肽Y（NPY）敏感性增加的发展同时发生。为了追踪NPY超敏反应的病因，我们评估了（1）下丘脑NPY Y1和Y5受体（R）基因的表达，以及（2）脂肪细胞产生的激素瘦素抑制作用改变的可能性。成年雄性大鼠通过向VMN双侧微量注射COL（4微克/侧）而变得食欲亢进。我们观察到，通过核糖核酸酶保护试验测量，在注射COL的大鼠中，下丘脑NPY Y1 mRNA水平在第2天显著升高，并在第4天恢复到对照水平。对NPY Y5R mRNA的影响不那么明确。有趣的是，血清瘦素水平随着食欲亢进和体重增加而升高，从而增加了对内源性瘦素对食物摄入抑制作用产生抵抗的可能性。实际上，向脑室注射7微克人重组瘦素（该剂量可减少正常和禁食大鼠的每日食物摄入量），在减轻COL处理大鼠的食欲亢进方面完全无效。这些结果表明，VMN中信号传导中断诱导的短暂食欲亢进可能是由于对NPY的敏感性增加所致，而这可能部分是由参与调节摄食行为的下丘脑部位NPY Y1R表达增加所引起的。此外，瘦素释放增加以及同时出现的瘦素抵抗表明，正常运作的VMN对于瘦素对食物摄入的中枢抑制作用可能是必需的。
