Ghrelin and the Growth Hormone Neuroendocrine Axis

摘要

Growth hormone (GH) is an anabolic hormone that is essential for normal linear growth and has important metabolic effects throughout life. The ultradian rhythm of GH secretion is generated by the intricate patterned release of two hy-pothalamic hormones, somatostatin (SRIF) and GH-releasing hormone (GHRH), acting both at the level of the pituitary gland and within the central nervous system. The recent discovery of ghrelin, a novel GH-releasing peptide identified as the endogenous ligand for the GH-secretagogue receptor (GHS-R) and shown to induce a positive energy balance, suggests the existence of an additional neuroendocrine pathway for GH control. To further understand how ghrelin interacts with the classical GHRH/SRIF neuronal system in GH regulation, we used a combined physiological and histochemical approach. Our physiologic studies of the effects of ghrelin on spontaneous pulsatile GH secretion in conscious, free-moving rats demonstrate that: 1) ghrelin, administered peripherally, exerts potent, time-dependent GH-releasing activity under physiological conditions; 2) ghrelin is a functional antagonist of SRIF, but its GH-releasing activity is not dependent on inhibiting endogenous SRIF release; 3) SRIF antagonizes the action of ghrelin acting at the level of the pituitary gland; and 4) the GH response to ghrelin requires an intact endogenous GHRH system. Our dual chromogenic and autoradi-ographic in situ hybridization experiments provide anatomical evidence that ghrelin may directly modulate GHRH mRNA- and NPY mRNA-containing neurons in the hypothalamic arcuate nucleus, but Xhst SRIF mRNA-expressing cells in the periventricular nucleus are not major direct targets for ghrelin. Together, these findings support the notion that ghrelin may be a critical hormonal signal of nutritional status to the GH neuroendocrine axis serving to integrate energy balance and the growth process.