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This Article Full Text Full Text (PDF) All Versions of this Article: JME-09-0023v1 43/3/105    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wagner, C. Articles by Tannenbaum, G. S PubMed PubMed Citation Articles by Wagner, C. Articles by Tannenbaum, G. S

Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland
¹ Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
² Department of Physiology, McGill University, Montreal, Québec, Canada H3G 1Y6
³ Neuropeptide Physiology Laboratory, Departments of Pediatrics and Neurology and Neurosurgery, McGill University-Montreal Children's Hospital Research Institute, McGill University, 2300 Tupper Street, PT 227, Montreal, Québec, Canada H3H 1P3

(Correspondence should be addressed to G S Tannenbaum; Email: gloria.tannenbaum{at}mcgill.ca)

Growth hormone (GH) is secreted in a pulsatile fashion from the pituitary gland into the circulation. Release is governed by two hypothalamic neuropeptides, growth hormone-releasing hormone (GHRH) and somatostatin (SRIF), resulting in secretion episodes with a periodicity of 3.3 h in the male rat. Ghrelin is an additional recently identified potent GH-secretagogue. However, its in vivo interactions with the GH neuroendocrine axis remain to be elucidated. Moreover, two different sites of ghrelin synthesis are involved, the stomach and the hypothalamus. We used our previously developed core model of GH oscillations and added the sites of ghrelin action at the pituitary and in the hypothalamus. With this extended model, we simulated the effects of central and peripheral ghrelin injections, monitored the GH profile and compared it with existing experimental results. Systemically administered ghrelin elicits a GH pulse independent of SRIF, but only in the presence of GHRH. The peripheral ghrelin signal is mediated to the brain via the vagus nerve, where it augments the release of GHRH and stimulates the secretion of neuropeptide-Y (NPY). By contrast, centrally administered ghrelin initiates a GH pulse by increasing the GHRH level and by antagonizing the SRIF block at the pituitary. In addition, NPY neurons are activated, which trigger a delayed SRIF surge. The major novel features of the present model are a) the role played by NPY, and b) the dissimilar functions of ghrelin in the hypothalamus and at the pituitary. Furthermore, the predictions of the model were experimentally examined and confirmed.