Leptin Is a Potent Stimulator of Spontaneous Pulsatile Growth Hormone (GH) Secretion and the GH Response to GH-Releasing Hormone*
Leptin Is a Potent Stimulator of Spontaneous Pulsatile Growth Hormone (GH) Secretion and the GH Response to GH-Releasing Hormone*
复制标题
瘦素是自发性搏动生长激素 (GH) 分泌和 GH 对 GH 释放激素反应的有效刺激剂*
DOI：
10.1210/en.139.9.3871
复制
发表时间：
1998
影响因子：
5
通讯作者：
M. Lapointe
中科院分区：
文献类型：
--
作者：
G. Tannenbaum;W. Gurd;M. Lapointe
脉动的生长激素分泌对营养状态的扰动非常敏感，但其潜在的机制在很大程度上是未知的。瘦素是最近发现的一种脂肪细胞激素，被认为是能量储存的传感器，并在大脑水平上调节身体质量、食欲和新陈代谢。瘦素受体在下丘脑参与生长激素调节的核团中大量表达，提示瘦素可能是正常动物生长激素神经内分泌轴的重要激素信号。为了验证这一假说，我们检测了脑室注射重组小鼠瘦素，每天1.2 mg，连续7天，对自由活动成年雄性大鼠自发和生长激素释放激素(GHRH)刺激的GH分泌的影响。伴随着对摄食量、体重和基础血浆胰岛素样生长因子I、胰岛素和血糖浓度的抑制，中心输注瘦素导致GH脉搏幅度增加2~3倍，GH最低值增加5倍，6h GH反应曲线下积分面积增加2~3倍(P，0.001)。脑室注射Leptin也使GHRH诱导的GH释放在GH谷期增加3~4倍(P<0.01)。这些研究表明，瘦素对自发性搏动性GH分泌和GH对GHRH的反应都有很强的刺激作用。这些结果表明，瘦素的生长激素释放活性至少部分是通过抑制下丘脑生长抑素的释放来实现的。因此，瘦素可能是神经内分泌调节脉动性生长激素分泌中营养状态的关键激素信号。(内分泌学139：3871-3875,1998)生长激素神经内分泌轴对营养状态的变化非常敏感。生长激素释放的自发脉冲明显受到抑制，以应对一系列代谢扰动，包括食物缺乏、胰岛素缺乏性糖尿病和细胞内血糖减少(见参考文献)。1个供审查)。此外，在人类(2)和实验动物模型(3，4)中，肥胖都与自发性和生长激素释放激素(GHRH)诱导的GH分泌受损有关。这种营养不良可能导致脂肪分解减少，并可能使潜在的肥胖状态持续存在。然而，代谢和营养因素对生长激素分泌的神经内分泌调节的机制在很大程度上是未知的。其中一个可能的调节因素是瘦素，这是最近发现的一种脂肪细胞激素，是ob基因的蛋白质产物(6)。瘦素由脂肪细胞分泌，被认为是能量储存的传感器，并在大脑水平上调节食欲和新陈代谢(7，8)。事实上，瘦素的血液浓度在卡路里补充期间增加，在禁食期间减少(9)。迅速积累的数据表明，瘦素是营养和几个神经内分泌系统之间的体液联系(10-13)。瘦素受体在大脑中表达的发现证实了这一假说。事实上，瘦素受体在已知参与生长激素调节的下丘脑核团中大量表达，包括弓状核和脑室周围核(15，16)，全身注射瘦素可诱导弓状核中的Fos蛋白(17)。最近的双标记研究表明，在弓状GHRH神经元中存在瘦素受体免疫反应。这些观察结果表明，瘦素可能是调节GH搏动性分泌的重要激素信号。为了验证这一假设，我们检测了脑室(Icv)注射瘦素对正常自由活动大鼠自发和GHRH刺激的GH分泌的影响。还监测了食物摄入量、体重和血浆中胰岛素样生长因子I(IGF-I)、胰岛素和葡萄糖的浓度。材料与方法动物和实验方法成年雄性SD大鼠(225-300g)购自加拿大Charles River(St.Constant，加拿大)，分别置于12h光照、12h暗周期(灯亮，0600~1800h)的温度(226.1℃)和湿度控制的房间中。普里纳鼠食(密苏里州圣路易斯市拉尔斯顿普里纳)和自来水可以随意提供。在戊巴比妥钠(50 mg/kg，ip)麻醉下，使用上述技术(19，20)植入慢性ICV和心内静脉插管。ICV插管的放置通过1998年3月25日接受ICV时对卡巴胆碱(100 ng/10ml)的阳性饮用反应来证实。请将所有信件和重印请求发送至：Gloria S.Tannenbaum博士，神经肽生理学实验室，麦吉尔大学-蒙特利尔儿童医院研究所，加拿大魁北克省蒙特利尔市塔珀街2300号，加拿大魁北克省蒙特利尔市H3H1P3。电子邮件：mcta@musica。Mcgill.ca.*这项工作得到了Grant MT-6837(对G.S.T.)的支持。来自加拿大医学研究委员会。†Chercheur de Carrière of the Fond de la Recherche en Santédu Québec.0013-7227/98/$03.00/0第139卷，第9号内分泌学，美国印刷。版权所有©1998，内分泌学会
Pulsatile GH secretion is exquisitely sensitive to perturbations in nutritional status, but the underlying mechanisms are largely unknown. Leptin, a recently discovered adipose cell hormone, is thought to be a sensor of energy stores and to regulate body mass, appetite, and metabolism at the level of the brain. Receptors for leptin are abundantly expressed in hypothalamic nuclei known to be involved in GH regulation, suggesting that leptin may serve as an important hormonal signal to the GH neuroendocrine axis in normal animals. To test this hypothesis, we examined the effects of intracerebroventricular infusion of recombinant murine leptin, at a dose of 1.2 mg/day for 7 days, on both spontaneous and GH-releasing hormone (GHRH)stimulated GH secretion in free-moving adult male rats. Concomitant with suppressive effects on food intake, body weight, and basal plasma insulin-like growth factor I, insulin, and glucose concentrations, central infusion of leptin resulted in a 2to 3-fold augmentation of GH pulse amplitude, 5-fold higher GH nadir levels, and a 2to 3-fold increase in the integrated area under the 6-h GH response curve compared with those in vehicle-infused controls (P , 0.001). The intracerebroventricular infusion of leptin also produced a 3to 4-fold increase in GHRH-induced GH release at GH trough times (P , 0.01). These studies demonstrate a potent stimulatory action of leptin on both spontaneous pulsatile GH secretion and the GH response to GHRH. The results suggest that the GH-releasing activity of leptin is mediated, at least in part, by an inhibition of hypothalamic somatostatin release. Thus, leptin may be a critical hormonal signal of nutritional status in the neuroendocrine regulation of pulsatile GH secretion. (Endocrinology 139: 3871–3875, 1998) T GH neuroendocrine axis is exquisitely sensitive to changes in nutritional status. Spontaneous pulses of GH release are markedly suppressed in response to a whole host of metabolic perturbations, including food deprivation, insulinopenic diabetes, and intracellular glucopenia (see Ref. 1 for review). Furthermore, obesity is associated with an impairment of both spontaneous and GH-releasing hormone (GHRH)-induced GH secretion in both humans (2) and experimental animal models (3, 4). This hyposomatotropism probably results in decreased lipolysis (5) and may serve to perpetuate the underlying obese state. However, the mechanisms by which metabolic and nutritional factors contribute to the neuroendocrine regulation of GH secretion are largely unknown. One such possible regulator is leptin, the recently discovered adipose cell hormone that is the protein product of the ob gene (6). Leptin is secreted from adipocytes and is thought to be a sensor of energy stores and to regulate appetite and metabolism at the level of the brain (7, 8). Indeed, blood concentrations of leptin increase during times of caloric repletion and decrease during fasting (9). Rapidly accumulating data have implicated leptin as a humoral link between nutrition and several neuroendocrine systems (10–13). The discovery of leptin receptor expression in the brain (14) lends credence to this hypothesis. In fact, receptors for leptin are abundantly expressed in those hypothalamic nuclei known to be involved in GH regulation, including the arcuate and periventricular nuclei (15, 16), and systemic injection of leptin induces Fos protein in the arcuate nucleus (17). Recent double labeling studies have shown the presence of leptin receptor immunoreactivity in arcuate GHRHcontaining neurons (18). These observations suggest that leptin may serve as an important hormonal signal in the regulation of pulsatile GH secretion. To test this hypothesis, we examined the effects of intracerebroventricular (icv) infusion of leptin on both spontaneous and GHRH-stimulated GH secretion in normal freemoving rats. Food intake, body weight, and plasma concentrations of insulin-like growth factor I (IGF-I), insulin, and glucose were also monitored. Materials and Methods Animals and experimental procedure Adult male Sprague-Dawley rats (225–300 g) were purchased from Charles River Canada (St. Constant, Canada) and individually housed on a 12-h light, 12-h dark cycle (lights on, 0600–1800 h) in a temperature (22 6 1 C)and humidity-controlled room. Purina rat chow (RalstonPurina, St. Louis, MO) and tap water were available ad libitum. Chronic icv and intracardiac venous cannulas were implanted under sodium pentobarbitol (50 mg/kg, ip) anesthesia using previously described techniques (19, 20). The placement of the icv cannula was verified by both a positive drinking response to carbachol (100 ng/10 ml) icv inReceived March 25, 1998. Address all correspondence and requests for reprints to: Dr. Gloria S. Tannenbaum, Neuropeptide Physiology Laboratory, McGill University-Montreal Children’s Hospital Research Institute, 2300 Tupper Street, Montreal, Québec, Canada H3H 1P3. E-mail: mcta@musica. mcgill.ca. * This work was supported by Grant MT-6837 (to G.S.T.) from the Medical Research Council of Canada. † Chercheur de Carrière of the Fonds de la Recherche en Santé du Québec. 0013-7227/98/$03.00/0 Vol. 139, No. 9 Endocrinology Printed in U.S.A. Copyright © 1998 by The Endocrine Society
登录
查看更多内容
影响因子：
15.9
作者：
Schwartz, MW;Seeley, RJ;Baskin, DG
通讯作者：
Baskin, DG
瘦素对正常大鼠胰岛素敏感性的影响。
DOI：
10.1210/endo.138.8.5327
发表时间：
1997
期刊：
Endocrinology.
影响因子：
--
作者：
Sivitz,WI;Walsh,SA;Morgan,DA;Thomas,MJ;Haynes,WG
通讯作者：
Haynes,WG
神经肽 Y 通过刺激生长抑素释放来抑制生长激素释放，具有显着的生理作用。
影响因子：
4.8
作者：
Rettori,V;Milenkovic,L;Aguila,MC;McCann,SM
通讯作者：
McCann,SM
DOI：
10.1073/pnas.93.25.14795
发表时间：
1996-12-10
影响因子：
11.1
作者：
Chen, GX;Koyama, K;Unger, RH
通讯作者：
Unger, RH
大鼠食物剥夺对下丘脑生长激素释放因子和生长抑素表达的影响。
影响因子：
4.8
作者：
Bruno,JF;Olchovsky,D;White,JD;Leidy,JW;Song,J;Berelowitz,M
通讯作者：
Berelowitz,M