Unnatural Growth Hormone-Releasing Peptide Begets Natural Ghrelin

Unnatural GH-releasing peptide (GHRP) finally has evolved into the highly probable natural GHRP designated ghrelin. The beginning was in 1976, the receptor in 1996, and, at last, the endogenous hormone in 1999 (1–3). Despite the artificiality of the unnatural GHRPs, results of many talented investigators worldwide are responsible for sustaining the interest in the GHRP/GH secretagogue (GHS) system. The recent isolation and cloning of both rat and human ghrelin certainly are major milestones in the GHRP story. Ghrelin is a novel molecule with a molecular weight of 3314, which is very possibly more readily biodegradable than GHRH and, thus, may have been the reason GHRH was isolated first. It is a relatively charged, linear, non-C-terminal amidated 28 amino acid peptide with a significant number of chemical functional groups. Unique and a first in mammalian peptides is the posttranslation addition of a straight chain octanoyl group covalently linked to the hydroxyl group of Ser (3) via an ester linkage. The n-octanoyl group adds a hydrophobic property to the N terminus that may facilitate entry and distribution in the brain. Without octanoylation, ghrelin is biologically inactive. As do unnatural GHRPs, natural ghrelin binds with high affinity and specificity to the 7 transmembrane G protein-coupled receptor. To reveal the interrelationships of the chemistry of ghrelin and the many chemically diverse small unnatural peptidyl, partial peptidyl, and nonpeptidyl GHRP/GHSs should impart new understanding and dimension to the structure-activity relationship of peptides (4). Seemingly it is a strong precedent for the feasibility of developing bioactive small molecules that mimic the action of larger peptides. More important, in the future this may even include GHRH 1–44NH2. In addition, a limitation of the purely gene approach for the discovery of biologically active peptides is underscored by the chemical structure of ghrelin. Involvement in the regulation of GH secretion is the way the GHRP story began and mainly has proceeded, but over time other actions have become of special interest. The recent outstanding accomplishment of Kojima et al. (3) on the isolation and identification of ghrelin and secretion of ghrelin primarily from the fundus of the stomach in addition to the hypothalamus has allowed new and intriguing dimensions to arise on the possible overall physiological role of the ghrelin/GHRP system. The dual action on GH secretion and food intake in conjunction with the dual anatomical localization of ghrelin in the stomach and hypothalamus present an immediate question about the interdependency of these actions and the site of origin. After intracerebroventricular (icv) ghrelin administration to rats, Date et al. (5) demonstrated that GH release was dose-relatedly increased, including even low dosages of ghrelin. The effectiveness of the GHRPs and now ghrelin on increased food intake in rats and mice has been well established (6–8). After a single icv injection of ghrelin or neuropeptide Y (NPY) to rats, Wren et al. (7) found a similar effect of the two peptides on food intake that was prolonged in that the effect was sustained over 24 h. In this study, icv GHRP-6 also increased food intake but of shorter duration; however, this may be related to differences in peptide potency and dosage. After a single ip injection of ghrelin or GHRP to satiated rats, food intake was immediately increased during the first hour. As the authors stated, the orexigenic activity of ghrelin after peripheral administration was considerably important in that other hypothalamic peptides that alter food intake are ineffective by this route of administration. Despite the findings that GHRP/ghrelin receptors are coexpressed in NPY neurons, GHRP stimulates c-fos in these neurons, and that NPY is a potent orexigenic peptide, it remains questionable whether the GHRP/ghrelin effect on food intake is mediated via NPY (7–9). Particularly relevant, Kamegai et al. (10) reported that icv ghrelin increased the expression of the orexigenic agouti-related protein rather than NPY in the hypothalamic arcuate nucleus. The recent report by Takaya et al. (11) entitled “Ghrelin strongly stimulates GH release in humans” demonstrates the high potency and the extraordinary amount of GH released by ghrelin, which is also characteristic of the GHRP/GHSs. The amount of GH released is much greater than that induced by maximal dosages of GHRH, indicating a distinctive pharmacological action. In these studies in normal young men, the peak GH rise to iv bolus dosages of 0.2, 1, and 5 mg/kg was 43, 81, and 107, respectively, whereas the GH area under the curve was 2451, 6217, and 9581, respectively. Essentially, the same GH responses have been obtained with GHRP-2 at comparable iv bolus dosages in normal young Received October 25, 2000. Revision received December 8, 2000. Accepted December 20, 2000. Address correspondence and requests for reprints to: Cyril Y. Bowers, M.D., Endocrine Section, Tulane University School of Medicine, 1430 Tulane Avenue, SL53, New Orleans, Louisiana 70112-2699. 0021-972X/01/$03.00/0 Vol. 86, No. 4 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society