Gastroenterology

Gastroenterology

Volume 125, Issue 5, November 2003, Pages 1492-1502
Gastroenterology

Special report and review
Ghrelin for the gastroenterologist: history and potential

https://doi.org/10.1016/j.gastro.2003.06.002Get rights and content

Abstract

Ghrelin, a novel 28—amino acid orexigenic peptide discovered in 1999, has given us further insights into the control of energy homeostasis and growth hormone secretion. As a natural endogenous ligand of the growth hormone secretagogue receptor, it potently stimulates growth hormone release but is also implicated in many other homeostatic mechanisms. Released from the stomach, it stimulates lactotroph and corticotroph secretion, increases appetite and adiposity, has beneficial hemodynamic effects, has prokinetic and gastric acid secretory functions in the stomach, and may even be implicated in sleep. As advances in the understanding of appetite and obesity are made, it is timely to review the possibly central role of ghrelin in these physiological and pathophysiological states. This review will discuss the recent literature concerning this exciting novel neuropeptide and discuss the possible therapeutic possibilities it may open up to us.

Section snippets

Distribution and localization

In their original experiments, Kojima et al.7 showed that ghrelin was present in large amounts in rat stomach. Taking this together with the fact that ghrelin, when injected intravenously, induces GH release, they proposed that ghrelin was secreted in the stomach and circulated in the bloodstream to act on the pituitary gland. They also showed ghrelin-immunoreactive neurons in the hypothalamic arcuate nucleus and suggested that ghrelin in the arcuate nucleus may either act on the hypothalamus

Ghrelin and growth hormone secretion

Having identified the natural ligand for GHS-R and having shown stimulation of GH secretion by ghrelin in the rat, investigators showed the potency of the peptide on GH release in the same species.24, 25, 26 Human studies have shown a dose-dependent stimulation of GH release with both intravenous infusions and boluses of ghrelin.26, 27, 28 There were no significant adverse effects with doses of up to 500 μg.27 As well as GH release, there were increases in prolactin,27, 28 adrenocorticotropic

Other endocrine activities

As well as the marked increase in GH secretion elicited by ghrelin, there are effects on corticotroph and lactotroph secretion,26, 28, 38, 39 and ghrelin may play a role in glucose homeostasis and insulin secretion.20, 44, 45, 46 Ghrelin administration leads to an increase in prolactin, adrenocorticotropic hormone, cortisol, and aldosterone through mechanisms that are not yet clear.47, 48, 49, 50, 51 It has been suggested that some of the adrenocorticotropic hormone release may depend on a

Effects of ghrelin on feeding and energy homeostasis

During study of synthetic GHSs, it was noted that there was a short-lived increase in appetite after their acute administration,60, 61 and weight gain was noted with chronic systemic administration to immature rodents.3 Several investigators showed that either ICV or intraperitoneal ghrelin stimulated food intake as well as GH secretion in rats25, 26, 62; the orexigenic effect was comparable with that of neuropeptide Y (NPY).63, 64 Later experiments in volunteers by Wren et al.65 showed that

Obesity and eating disorders

Taken cumulatively, these findings suggest that ghrelin is up-regulated under conditions of negative energy balance and down-regulated in the setting of positive energy balance. The fact that ghrelin plasma levels are high in anorexia nervosa and low in obesity has led to speculation regarding a possible role in the pathophysiology of obesity.93 Several studies have established that plasma ghrelin levels are inversely correlated with body mass index (BMI),76, 93, 94, 95, 96 suggesting ghrelin

Cardiovascular and other effects of ghrelin

Previous work with GH and GHS has suggested beneficial hemodynamic effects. GH and insulin-like growth factor-I are essential for both skeletal and myocardial growth106 and may be beneficial in some patients with cardiac failure.107 GHS-R is abundantly expressed in many tissues, including the heart and blood vessels,5, 19, 108 and stimulation of GHS-R prevents cardiac damage after ischemia-reperfusion injury in hypophysectomized rats.109 Hence, it seemed likely that ghrelin would have

Effect of ghrelin on gastric motility and gastric acid secretion

After the initial discovery of ghrelin, Tomasetto et al.8 named the peptide the “motilin-related peptide” because of its structural homology with motilin. The aim of their study was to look for new proteins with expression restricted to the gastric epithelium that may provide insight to the differentiation and function of the gastric unit. They identified a novel mouse cDNA, m46, that encodes a peptide of 117 amino acids whose primary sequence is weakly similar to that of prepromotilin (22%

Conclusions

The discovery of ghrelin as an endogenous ligand for the GHS-R and the subsequent work described previously has widened our understanding of the control of GH secretion and energy homeostasis. Ghrelin increases feeding and weight gain and may have a role to play in the treatment and prevention of obesity; it may also offer a novel therapeutic strategy for the treatment of cancer cachexia. Its role as a prokinetic is not well established in humans, but further research may lead to advances in

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