Document Detail

The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system.
MedLine Citation:
PMID:  19734277     Owner:  NLM     Status:  MEDLINE    
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.
J Roa; D Garcia-Galiano; L Varela; M A S?nchez-Garrido; R Pineda; J M Castellano; F Ruiz-Pino; M Romero; E Aguilar; M L?pez; F Gaytan; C Di?guez; L Pinilla; M Tena-Sempere
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-04
Journal Detail:
Title:  Endocrinology     Volume:  150     ISSN:  1945-7170     ISO Abbreviation:  Endocrinology     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-22     Completed Date:  2009-11-16     Revised Date:  2010-04-12    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5016-26     Citation Subset:  AIM; IM    
Physiology Section, Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of C?rdoba, Avda. Men?ndez Pidal s/n, 14004 C?rdoba, Spain.
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MeSH Terms
Gene Expression Regulation, Developmental*
Hypothalamus / enzymology*,  growth & development,  metabolism
Leucine / metabolism
Luteinizing Hormone / metabolism
Protein Kinases / genetics,  metabolism*
Proteins / genetics*,  metabolism
Rats, Wistar
Signal Transduction
Reg. No./Substance:
0/Kiss1 protein, rat; 0/Proteins; 61-90-5/Leucine; 9002-67-9/Luteinizing Hormone; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein

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