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Editorial |
Medical Department M Aarhus University Hospital DK-8000 Aarhus, Denmark
Address all correspondence and requests for reprints to: Jens Otto Lunde Jørgensen, Medical Department M, Aarhus University Hospital, DK-8000 Aarhus, Denmark.
Ghrelin is the long-awaited endogenous ligand for the GH secretagogue (GHS) receptor (GHS-R). The natural history of this hormone is just in its beginning, but it is already filled with surprises. The starting point was the dedicated search by Bowers and colleagues (1) for a GH-stimulating factor. One could argue that they didn’t find what they were looking for because they were overtaken by the discovery of GH-releasing hormone (GHRH), which was identified from two patients with acromegaly caused by ectopic GHRH production. Nevertheless, the compounds studied by Bowers remained potent independent stimulators of GH release, which subsequently led to the development of so-called GH secretagogues for oral administration (2).
The next milestone was the characterization by Smith et al. (3) of the endogenous GHS-R. As expected, the receptor was abundant in the hypothalamus and on the pituitary gland, and it was anticipated that the endogenous ligand would be found in the central nervous system. It was therefore sensational when Kojima et al. (4) discovered a ligand in the gastric mucosa. The molecule is a 28-amino acid peptide with a unique n-octanoyl ester at its third serine residue. The etymology is also unique, because "ghre" is the root of the word grow, but ghrelin evidently also connotes GH release. The beauty and ambiguity of the name was almost prophetic when considering the revelations of the diverse and complicated physiology of this peptide. Many aspects have recently been reviewed (5), but some of them merit repetition. As expected, exogenous ghrelin strongly stimulates GH release in humans (6), but it has proven difficult to demonstrate that circulating endogenous ghrelin levels regulate pituitary GH secretion. Conditions such as physical exercise, fasting, and insulin-induced hypoglycemia, all of which stimulate GH secretion, are not preceded by detectable elevations in systemic ghrelin levels (7, 8, 9), and ghrelin levels are only moderately perturbed in patients with GH deficiency and acromegaly (7, 10). One explanation could be that the data rely on measurement of total ghrelin levels of which the majority is nonacylated, which does not bind to the GHS-R (5). An assay for measuring acylated ghrelin, which is available, could provide a more precise tool for investigating the physiological interplay between the secretion of gut-derived ghrelin and pituitary GH, respectively. Alternatively, it is possible that GH is stimulated by ghrelin derived from the brain or the pituitary gland. A third and more heretical theory would be that the role of endogenous gut-derived ghrelin is not primarily to provoke GH secretion.
At present the stimulatory effects of ghrelin on appetite and fat gain are probably the most publicized topics within the area. Before that, orexigenic effects of GHS administration in rodent models were reported together with similar, but more anecdotal data in humans (5). It was subsequently reported that systemic (11) as well as intracerebroventricular (11, 12) ghrelin administration stimulated appetite and fat accretion in rats. Indeed, ghrelin is considered the first known circulating orexigenic compound. In human subjects, iv infusion of ghrelin also stimulates food intake (13). In addition, there is circumstantial evidence in humans to suggest that circulating ghrelin, which rises preprandial and is suppressed by food intake, may function as a meal initiator (14). The underlying mechanisms are not fully elucidated, but they seem to involve activation of neuropeptide Y and agouti-related peptide containing neurons in the arcuate nucleus (12, 15), which are well-known orexigenic pathways that also contain GHS-R. Peripheral actions of ghrelin on substrate metabolism are also reported, but such effects are difficult to study in vivo, because infusion of ghrelin also stimulates the release of GH and ACTH. In this regard, hypopituitary patients substituted with GH and hydrocortisone may constitute a model for defining the direct metabolic effects of circulating ghrelin.
In this issue of the Journal, gastrokinetic effects are added to the expanding portfolio of ghrelin (16). In a double-blind crossover design, Levin et al. (16) report that iv infusion of ghrelin significantly increases gastric motility in healthy human subjects. The rate of solid gastric emptying was assayed scintigraphically during 180 min after intake of a radioactively labeled omelet. The ghrelin-induced increase in gastric motility was associated with a more rapid and pronounced postprandial increase in plasma cholecystokinin and glucagon-like peptide 1 levels, whereas ghrelin had no impact on the circulating levels of either motilin or peptide YY. Consistent with previous findings, ghrelin infusion also stimulated appetite and decreased satiety. The gastrokinetic data are in accordance with studies in animals (17) and in patients with idiopathic and diabetic gastroparesis (18). By contrast, one previous study, which was the first to demonstrate an orexigenic effect of ghrelin in healthy human subjects, could not detect an effect on gastric emptying (13). In the latter study, the ghrelin infusion rate was 50% lower, and it was started 2 h before testing gastric emptying by means of the paracetamol absorption test. The results of the present study, however, appear convincing, and the authors state that their scintigraphic method is considered the gold standard. Levin et al. (16) also report that gastric emptying was unaltered in six hypopituitary adult GH-deficient patients before and after 6 months of GH replacement therapy (16). Based on this, it is concluded that the gastrokinetic effects of ghrelin are not secondary to stimulation of GH release. A more appropriate way to rule out an effect of GH would be to compare the effect of ghrelin vs. saline on gastric emptying in patients on stable GH replacement. Considering the underlying mechanisms, the authors documented expression of the GHS-R in the human stomach, which makes direct effects possible. Motilin, which is a known accelerator of gastric emptying, was not stimulated by infusion of ghrelin. Interestingly, motilin is structurally related to ghrelin, and the motilin receptor was initially identified as an orphan receptor belonging to the GHS-R "family" (reviewed in Ref. 19). The observed ghrelin-induced increase in plasma levels of glucagon-like peptide 1 and cholecystokinin was interpreted as a compensatory response, because these hormones are known to inhibit gastric emptying. Apart from direct effects in the stomach, other studies have suggested that the gastrokinetic effects of ghrelin may be mediated by activation of efferent central pathways and vagal afferents (reviewed in Ref. 19).
As also discussed by the authors, it is tempting to speculate that the increase in gastric emptying might contribute to the orexigenic effects of ghrelin, because these features are positively correlated in humans. It is, however, important to recall that the gastrokinetic effects were obtained with constant infusion of ghrelin in pharmacological doses, and the physiological role of endogenous ghrelin in gastric emptying remains to be demonstrated. In fact, normal gastric emptying has recently been reported in ghrelin knockout mice model (20).
In summary, the present study convincingly corroborates yet another effect of ghrelin. Space constraint has made it impossible to cover all aspects of this expanding field, which also includes interaction with insulin secretion and fat metabolism, cardiovascular function, and central effects on sleep and behavior (5). The most recent surprise has been that another peptide named obestatin, which is derived from proghrelin, binds to an orphan G coupled receptor and induces effects in rats that are opposite to those of ghrelin (21).
The potential therapeutic implications of ghrelin agonists and antagonists are many: amplification of GH release, treatment of eating disorders and obesity, and treatment of gastroparesis. That vista will probably also be paved with unexpected data. The history of ghrelin is also a lesson for providers of research grants. Give the right people—tomorrow’s Bowers, Smith, and Kojima—the opportunity to seek, and they shall find. And learn to accept, as a twist of science, that you seldom find exactly what you were looking for.
Footnotes
Abbreviations: GHS, GH secretagogue; GHS-R, GHS receptor.
Received June 20, 2006.
Accepted July 14, 2006.
References
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