Palmiter R D, Erickson J C, Hollopeter G, Baraban S C, Schwartz M W
Howard Hughes Medical Institute, University of Washington, Seattle 98195, USA.
Recent Prog Horm Res. 1998;53:163-99.
Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
神经肽Y（NPY）是一种由外周和中枢神经系统的神经元分泌的含36个氨基酸的神经调质，与许多生理过程的调控有关。我们已开始通过研究因基因失活而无法产生NPY的小鼠，来探究其在食欲调节、行为和兴奋性毒性方面的作用。这些突变小鼠在标准饲养条件下饲养时表现相当正常。尽管有大量证据表明NPY在刺激食欲方面起核心作用，但NPY缺乏的小鼠进食正常、生长正常，禁食后重新进食也正常。此外，它们对禁食的所有内分泌反应均正常。NPY基因敲除小鼠对饮食诱导的肥胖、化学诱导的肥胖（谷氨酸钠和金硫葡萄糖）以及基于遗传的肥胖（致死性黄色刺鼠，Ay；解偶联蛋白 - 白喉毒素转基因小鼠，UCP - DT）的反应均正常。然而，NPY缺乏确实部分改善了ob/ob小鼠的肥胖以及瘦素缺乏的所有不良内分泌影响。NPY基因敲除小鼠以及同时缺乏NPY和瘦素的小鼠对瘦素更敏感，这表明NPY通常可能对瘦素介导的饱腹感信号具有紧张性抑制作用。NPY基因敲除小鼠对注射的NPY表现出正常的贪食反应。因此，我们观察到NPY在体重调节中起作用的唯一情况是在完全缺乏瘦素的背景下——此时NPY的缺失是有益的。NPY基因敲除小鼠的活动和一般行为正常。它们似乎具有正常的空间和情境学习能力；然而，在某些情况下它们表现出更多焦虑。NPY基因敲除小鼠偶尔会出现自发的癫痫样发作。它们也较难终止由GABA受体拮抗剂或谷氨酸受体激动剂诱导的癫痫发作。这些观察结果与先前的数据一致，表明NPY在减轻兴奋性毒性方面起重要作用。
