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Comparative Analysis of the Effects of Ghrelin and Unacylated Ghrelin on Luteinizing Hormone Secretion in Male Rats

Department of Cell Biology, Physiology, and Immunology (A.C.M., R.F.-F., V.M.N., E.V., E.A., L.P., M.T.-S.), University of Córdoba, 14004 Córdoba, Spain; School of Biosciences (J.S.D., N.M.T., T.W.), Cardiff University, Cardiff CF10 3US, United Kingdom; and Department of Physiology (S.T., M.J.V., 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.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.

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