A Postweaning Reduction in Circulating Ghrelin Temporarily Alters Growth Hormone (GH) Responsiveness to GH-Releasing Hormone in Male Mice But Does Not Affect Somatic Growth
A Postweaning Reduction in Circulating Ghrelin Temporarily Alters Growth Hormone (GH) Responsiveness to GH-Releasing Hormone in Male Mice But Does Not Affect Somatic Growth
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DOI：
10.1210/en.2009-1040
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发表时间：
2010-04-01
期刊：
影响因子：
4.8
通讯作者：
Akamizu, Takashi
中科院分区：
文献类型：
--
作者：
Ariyasu, Hiroyuki;Iwakura, Hiroshi;Akamizu, Takashi
Ghrelin最初被认为是GH促分泌素受体的内源性配体。当外源性给药时，Ghrelin刺激生长激素的释放和食物的摄入。先前在没有Ghrelin基因缺失的小鼠中的报告质疑Ghrelin在GH/IGF-I轴调节中的生理作用，这些小鼠没有表现出生长或食欲受损。在本研究中，我们获得了一只在Ghrelin分泌细胞中表达人白喉毒素受体(DT)受体(DTR)基因的转基因小鼠[Ghrelin启动子DTR转基因小鼠(GPDTR-TG)]。给这只小鼠注射DT会以受控的方式去除Ghrelin分泌细胞。注射DT后，GPDTR-TG小鼠的Ghrelin分泌细胞被消融，血浆Ghrelin水平显著降低[非转基因小鼠，70.6+/-10.2fmol/mlvs.GPDTRTg，5.3+/-2.3fmol/ml]。为了阐明循环Ghrelin对GH分泌和身体生长的生理作用，对3周龄GPDTR-TG小鼠进行了DT治疗，每周2次，连续5wk。在5周龄时，雄性GPDTRTg小鼠对GHRH的反应显著低于野生型小鼠。然而，这些在8周龄时被正常化。相反，在雌性小鼠中，GPDTR-TG小鼠和对照组在5或8周龄时对GHRH的GH反应没有差异。在Ghrelin消融的小鼠中观察到了GHRH反应的性别差异。然而，GPDTR-TG小鼠没有表现出任何IGF-I水平的下降或任何生长迟缓。我们的结果有力地表明，循环中的Ghrelin在躯体生长中并不起关键作用。(内分泌学151：1743-1750,2010)
Ghrelin was initially identified as an endogenous ligand for the GH secretagogue receptor. When administrated exogenously, ghrelin stimulates GH release and food intake. Previous reports in ghrelin-null mice, which do not exhibit impaired growth nor appetite, question the physiologic role of ghrelin in the regulation of the GH/IGF-I axis. In this study, we generated a transgenic mouse that expresses human diphtheria toxin (DT) receptor (DTR) cDNA in ghrelin-secretion cells [ghrelin-promoter DTR-transgenic (GPDTR-Tg) mice]. Administration of DT to this mouse ablates ghrelin-secretion cells in a controlled manner. After injection of DT into GPDTR-Tg mice, ghrelin-secreting cells were ablated, and plasma levels of ghrelin were markedly decreased [nontransgenic litter-mates, 70.6 +/- 10.2 fmol/ml vs. GPDTR-Tg, 5.3 +/- 2.3 fmol/ml]. To elucidate the physiological roles of circulating ghrelin on GH secretion and somatic growth, 3-wk-old GPDTR-Tg mice were treated with DT twice a week for 5 wk. The GH responses to GHRH in male GPDTR-Tg mice were significantly lower than those in wild-type mice at 5 wk of age. However, those were normalized at 8 wk of age. In contrast, in female mice, there was no difference in GH response to GHRH between GPDTR-Tg mice and controls at 5 or 8 wk of age. The gender-dependent differences in response to GHRH were observed in ghrelin-ablated mice. However, GPDTR-Tg mice did not display any decreases in IGF-I levels or any growth retardation. Our results strongly suggest that circulating ghrelin does not play a crucial role in somatic growth. (Endocrinology 151: 1743-1750, 2010)