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The Mammalian Target of Rapamycin as Novel Central Regulator of Puberty Onset via Modulation of Hypothalamic Kiss1 System

Department of Cell Biology, Physiology, and Immunology (J.R., D.G.-G., M.A.S.-G., R.P., J.M.C., F.R.-P., M.R., E.A., F.G., L.P., M.T.-S.), University of Córdoba, Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (J.R., D.G.-G., L.V., M.A.S.-G., R.P., J.M.C., F.R.-P., M.R., E.A., M.L., F.G., C.D., L.P., M.T.-S.), and Instituto Maimónides de Investigaciones Biomédicas de Córdoba (E.A., M.T.-S.), 14004 Córdoba, Spain; and Department of Physiology (L.V., M.L., C.D.), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain

Address all correspondence and requests for reprints to: Manuel Tena-Sempere, Physiology Section, Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. E-mail: fi1tesem{at}uco.es.

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.