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This version published online on June 2, 2005
Endocrinology, doi:10.1210/en.2005-0337
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Submitted on March 21, 2005
Accepted on May 23, 2005

Changes in Hypothalamic KiSS-1 System and Restoration of Pubertal Activation of the Reproductive Axis by Kisspeptin in Undernutrition

J. M. Castellano, V. M. Navarro, R. Fernández-Fernández, R. Nogueiras, S. Tovar, J. Roa, M. J. Vazquez, E. Vigo, F. F. Casanueva, E. Aguilar, L. Pinilla, C. Dieguez, and M. Tena-Sempere*

Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; and Departments of Physiology and Medicine, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain

* To whom correspondence should be addressed. E-mail: fi1tesem{at}uco.es.

Activation of the gonadotropic axis critically depends on sufficient body energy stores and conditions of negative energy balance result in lack of puberty onset and reproductive failure. Recently, KiSS-1 gene derived kisspeptin, signaling through the G protein-coupled receptor GPR54, has been proven as pivotal regulator in the control of gonadotropin secretion and puberty. However, the impact of body energy status upon hypothalamic expression and function of this system remains unexplored. In this work, we evaluated the expression of KiSS-1 and GPR54 genes at the hypothalamus, as well as the ability of kisspeptin-10 to elicit gonadotropin-releasing hormone (GnRH) and LH (LH) secretion, in prepubertal rats under short-term fasting. In addition, we monitored the actions of kisspeptin on food intake, and the effects of its chronic administration upon puberty onset in undernutrition. Food deprivation induced a concomitant decrease in hypothalamic KiSS-1 and increase in GPR54 mRNA levels in prepubertal rats. In addition, LH responses to kisspeptin in vivo were enhanced, and its GnRH secretagogue action in vitro was sensitized, under fasting conditions. Central kisspeptin administration failed to change food intake patterns in animals fed ad libitum or after 12-h fasting. However, chronic treatment with kisspeptin was able to restore vaginal opening (in ~60%) and to elicit gonadotropin and estrogen responses in a model of undernutrition. In summary, our data are the first to evidence an interaction between energy status and hypothalamic KiSS-1 system, which may constitute a target for disruption (and eventual therapeutic intervention) of pubertal development in conditions of negative energy balance.
Key words: KiSS-1 • GPR54 • GnRH • gonadotropins • puberty • undernutrition • hypothalamus • rat




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