The hypothalamic mechanisms of the hypophysiotropic action of ghrelin

Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor, expressed in the hypothalamus and pituitary. Ghrelin, like synthetic GHSs, stimulates food intake and growth hormone (GH) release following systemic or intracerebroventricular administration. In addition to GH stimulation, ghrelin and synthetic GHSs are reported to stimulate the hypothalamo-pituitary-adrenal (HPA) axis in vivo. The aims of this study were to elucidate the hypothalamic mechanisms of the hypophysiotropic actions of ghrelin in vitro and to assess the relative contribution of hypothalamic and systemic actions of ghrelin on the HPA axis in vivo. Ghrelin (100 and 1,000 nM) stimulated significant release of GH-releasing hormone (GHRH) from hypothalamic explants (100 nM: 39.4 +/- 8.3 vs. basal 18.3 +/- 3.5 fmol/explant, n = 49, p < 0.05) but did not affect either basal or 28 mM KCl-stimulated somatostatin release. Ghrelin (10, 100 and 1,000 nM) stimulated the release of both corticotropin-releasing hormone (CRH) (100 nM: 6.0 +/- 0.8 vs. basal 4.2 +/- 0.5 pmol/explant, n = 49, p < 0.05) and arginine vasopressin (AVP) (100 nM: 49.2 +/- 5.9 vs. basal 35.0 +/- 3.3 fmol/explant, n = 48, p < 0.05), whilst ghrelin (100 and 1,000 nM) also stimulated the release of neuropeptide Y (NPY) (100 nM: 111.4 +/- 25.0 vs. basal 54.4 +/- 9.0 fmol/explant, n = 26, p < 0.05) from hypothalamic explants in vitro. The HPA axis was stimulated in vivo following acute intracerebroventricular administration of ghrelin 2 nmol [adrenocorticotropic hormone (ACTH) 38.2 +/- 3.9 vs. saline 18.2 +/- 2.0 pg/ml, p < 0.01; corticosterone 310.1 +/- 32.8 ng/ml vs. saline 167.4 +/- 40.7 ng/ml, p < 0.05], but not following intraperitoneal administration of ghrelin 30 nmol, suggesting a hypothalamic site of action. These data suggest that the mechanisms of GH and ACTH regulation by ghrelin may include hypothalamic release of GHRH, CRH, AVP and NPY.