The Mammalian Target of Rapamycin as Novel Central Regulator of Puberty Onset via Modulation of Hypothalamic Kiss1 System
The Mammalian Target of Rapamycin as Novel Central Regulator of Puberty Onset via Modulation of Hypothalamic Kiss1 System
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DOI：
10.1210/en.2009-0096
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发表时间：
2009-11-01
期刊：
影响因子：
4.8
通讯作者：
Tena-Sempere, M.
中科院分区：
文献类型：
--
作者：
Roa, J.;Garcia-Galiano, D.;Tena-Sempere, M.
哺乳动物雷帕霉素靶标 (mTOR) 是一种丝氨酸/苏氨酸激酶，可作为细胞能量状态的传感器和与细胞生长和增殖耦合的效应器。在下丘脑弓状核，mTOR 信号传导最近被提议作为瘦素对能量稳态和食物摄入影响的传感器。然而，中枢 mTOR 是否也参与生育力的代谢调节仍有待探索。我们在此提供了 mTOR 参与控制青春期开始和 LH 分泌的证据，可能是通过调节 Kiss1 的下丘脑表达。 L-亮氨酸急性激活 mTOR 可刺激青春期雌性大鼠的 LH 分泌，而慢性 L-亮氨酸输注可部分挽救因食物限制引起的促性腺激素低下状态。相反，雷帕霉素阻断中枢 mTOR 信号传导会导致青春期促性腺轴受到抑制，导致阴道开口显着延迟、LH 和雌二醇水平降低以及卵巢和子宫萎缩。 mTOR 失活也削弱了瘦素对食物限制女性青春期开始的积极影响。然而，在持续阻断 mTOR 后，GnRH/LH 系统保留了对卵巢切除术和 Kisspeptin-10 做出反应的能力，排除了雷帕霉素非特异性破坏 GnRH 功能的可能性。最后，mTOR 失活引起下丘脑 Kiss1 表达显着降低，弓状核处 Kiss1 mRNA 水平显着抑制。总而言之，我们的结果揭示了中枢 mTOR 信号在控制青春期开始和促性腺激素分泌中的作用，这种现象涉及 Kiss1 的调节，并可能有助于能量平衡与性腺激活和功能之间的功能耦合。 （内分泌学150：5016-5026，2009）
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that operates as sensor of cellular energy status and effector for its coupling to cell growth and proliferation. At the hypothalamic arcuate nucleus, mTOR signaling has been recently proposed as transducer for leptin effects on energy homeostasis and food intake. However, whether central mTOR also participates in metabolic regulation of fertility remains unexplored. We provide herein evidence for the involvement of mTOR in the control of puberty onset and LH secretion, likely via modulation of hypothalamic expression of Kiss1. Acute activation of mTOR by L-leucine stimulated LH secretion in pubertal female rats, whereas chronic L-leucine infusion partially rescued the state of hypogonadotropism induced by food restriction. Conversely, blockade of central mTOR signaling by rapamycin caused inhibition of the gonadotropic axis at puberty, with significantly delayed vaginal opening, decreased LH and estradiol levels, and ovarian and uterine atrophy. Inactivation of mTOR also blunted the positive effects of leptin on puberty onset in food-restricted females. Yet the GnRH/LH system retained their ability to respond to ovariectomy and kisspeptin-10 after sustained blockade of mTOR, ruling out the possibility of unspecific disruption of GnRH function by rapamycin. Finally, mTOR inactivation evoked a significant decrease of Kiss1 expression at the hypothalamus, with dramatic suppression of Kiss1 mRNA levels at the arcuate nucleus. Altogether our results unveil the role of central mTOR signaling in the control of puberty onset and gonadotropin secretion, a phenomenon that involves the regulation of Kiss1 and may contribute to the functional coupling between energy balance and gonadal activation and function. (Endocrinology 150: 5016-5026, 2009)