Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract

doi:10.1016/S1471-4892(02)00220-5

Current Opinion in Pharmacology

Volume 2, Issue 6, 1 December 2002, Pages 665-668

https://doi.org/10.1016/S1471-4892(02)00220-5 Get rights and content

Abstract

Recent identification of novel appetite-regulating hormones has revealed the complex interactions between these humoral factors in the regulation of feeding behavior in mammals. One such hormone is ghrelin, which is a natural ligand of the orphan growth hormone secretagogue receptor. Ghrelin was first purified from rat stomach and is able to stimulate growth hormone release from pituitary cells. Ghrelin is a peptide of 28 amino acids, in which Ser3 is modified by an n-octanoic acid. This modification is essential for the activity of ghrelin. The peptide regulates food intake by acting on the hypothalamic arcuate nucleus, which is a region known to control food intake. Thus, gastric ghrelin is an endogenous regulator of feeding behavior that is found in both peripheral tissues and the central nervous system.

Introduction

Feeding is a basic behavior that is necessary for organisms to survive. Long-term lack of food can lead to death. It is well accepted that appetite and feeding behavior are regulated by complex mechanisms in the central nervous system (CNS), particularly in the hypothalamus [1]. Removal of the lateral hypothalamus causes hypophagia (i.e. decreased feeding) and the animals eventually stop feeding, which leads to their death through severe weight loss. Conversely, removal of the ventromedial hypothalamus causes hyperphagia (i.e. increased feeding) and the animals exhibit increases in both the amount of food eaten and the time spent feeding. This leads to weight gain and severe obesity. Thus, feeding is regulated by a balance of stimulatory and inhibitory regions in the hypothalamus.

A close interaction between the brain and gastrointestinal gland in the regulation of feeding is probable because the gastrointestinal gland is in the main site of food digestion and nutrient absorption [2]. Therefore, the gastrointestinal gland is a suitable organ to monitor food amount and nutritional content.

The recent identification of appetite-regulating humoral factors revealed that regulatory mechanisms exist not only in the CNS but also in peripheral tissues 3., 4.. Leptin, which is secreted from adipose tissue, is an appetite-suppressing factor that transmits satiety signals to the brain [5]. Hunger signals originating from peripheral tissues, however, have not been identified. Ghrelin, a recently identified peptide hormone from the stomach, has both potent growth hormone (GH) releasing activity and appetite-stimulating activity 6••., 7••., 8•.. Ghrelin is secreted from the stomach and circulates in the bloodstream during fasting, which indicates that ghrelin transmits hunger signals from peripheral tissues to the CNS. In this review, we will provide an overview of ghrelin and our current understanding of the role of ghrelin in the regulation of feeding.

Section snippets

Structure of ghrelin

Ghrelin is the endogenous ligand for an orphan G-protein-coupled receptor, growth hormone secretagogue receptor (GHS-R) (Fig. 1) 6••., 9.. The name ghrelin is derived from the word ‘ghre’ in Proto-Indo European, which means ‘grow’ in modern English. Therefore, ghrelin is appropriately named because it stimulates GH release. Both rat and human ghrelin peptides consist of 28 amino acids, differing only in two residues. Both are modified at Ser3 by n-octanoic acid and this modification is

Tissue distribution of ghrelin

Ghrelin is produced mainly in the stomach 6••., 13.. In situ hybridization and immunohistochemical analyses indicated that ghrelin-containing cells are a distinct endocrine cell-type found in the mucosal epithelium of the stomach 14•., 15., 16.. These cells, known as X/A-like cells, contain round, compact, electron-dense granules that are filled with ghrelin. The fetal stomach does not express ghrelin but expression begins after birth [17]. Ghrelin is not secreted into gastrointestinal tracts

Growth hormone releasing activity of ghrelin

Ghrelin stimulates GH release both in vitro and in vivo 23., 24., 25., 26.. Ghrelin specifically stimulates GH release from primary pituitary cells in a dose-dependent manner, which indicates that ghrelin acts directly on the pituitary gland. Ghrelin is GH-specific because adrenocorticotropic hormone, thyroid-stimulating hormone, prolactin and follicle-stimulating hormone releases are not stimulated from primary pituitary cells.

Intravenous injection of ghrelin induces potent GH release both in

Appetite-stimulating effect of ghrelin

Ghrelin is appetite-stimulating when administered both centrally and peripherally 7••., 8•., 29., 30., 31•.. The hypothalamic arcuate nucleus is the main active site of ghrelin. The arcuate nucleus is also the target site of leptin, which is an appetite-suppressing hormone from adipose tissues [5], and neuropeptide Y (NPY) and agouti-related protein (AgRP), which are appetite-stimulating peptides produced in the arcuate nucleus. The appetite-stimulating effects of both NPY and AgRP are

Regulation of ghrelin secretion

Regulation of ghrelin secretion is controlled by feeding. Plasma ghrelin concentration is increased during periods of fasting and decreased after food intake 38•., 39., 40., 41.. It is not clear what factors are responsible for mediating the regulation of ghrelin secretion but blood glucose levels may be critical 7••., 42.. Indeed, oral or intravenous administration of glucose decreases plasma ghrelin concentration [7••]. Because gastric distention caused by water intake does not change ghrelin

Conclusion

Ghrelin is a gastrointestinal hormone that transmits appetite-related signals from peripheral organs to the brain. Ghrelin and leptin, which are appetite-stimulating and appetite-suppressing factors, respectively, circulate in the bloodstream and transmit fasting/satiety signals from peripheral tissues to appetite-regulatory regions in the hypothalamus by an unknown mechanism. Energy and metabolic processes in our body might also be controlled by a balance between negative and positive factors

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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Ghrelin(1–7)-NH₂ is the active N-terminal hepta-peptide of ghrelin as an agonist at the ghrelin receptor GHS-R1α. The biological functions of ghrelin(1–7)-NH₂ have not been well investigated. Therefore in this study, we were interested in exploring the effects and molecular mechanisms of ghrelin(1–7)-NH₂ in pain modulation at the supraspinal level using the tail withdrawal test in mice. Intracerebroventricular (i.c.v.) injection of ghrelin(1–7)-NH₂ (0.002, 0.02, 0.2 and 2 nmol/kg) induced a dose- and time-related antinociceptive effect. This antinociceptive effect was fully antagonized by co-injection with the GHS-R1α antagonist [D-Lys³]-GHRP-6, indicating that this effect induced by ghrelin(1–7)-NH₂ was mediated through the activation of GHS-R1α. Interestingly, naloxone, β-funaltrexamine, naloxonazine, and naltrindole, but not nor-binaltorphimine, could also antagonize the antinociceptive effect markedly, suggesting that OPRM (primary μ₁ subtype) and OPRD were involved in the antinociceptive response induced by ghrelin(1–7)-NH₂. Furthermore, the qRT-PCR and Western blot results indicated that both mRNA and protein levels of PENK and OPRD were up-regulated significantly. Using the fluorescence labeling method, our results showed that ghrelin(1–7)-NH₂ (i.c.v.) was mainly distributed at the dorsal 3rd ventricle and hippocampus where there are regions with high expressions of ghrelin, GHS-R1α and ORs. All these results indicated that ghrelin(1–7)-NH₂ initially activated the GHS-R1α, then activated the OPRM, as well as increased the release of endogenous PENK to activate of OPRD to produce antinociception. These results contributed to understanding the mechanisms of antinociception induced by ghrelin(1–7)-NH₂. Furthermore, ghrelin(1–7)-NH₂ as the active fragment of ghrelin may be a promising peptide for developing new analgesic drugs.
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Dietary fibers can be metabolized by special gut bacteria to produce SCFAs. SCFAs have been proven to decrease the plasma levels of des-acyl ghrelin and increase GLP-1 and PYY in humans and rodents (Cani et al., 2009; Delzenne, Cani, Daubioul, & Neyrinck, 2005; Kojima & Kangawa, 2002; Parnell & Reimer, 2009). Ghrelin, which is acylated via the actions of ghrelin O-acyltransferase, can decrease in response to prebiotic supplementation in rats and human subjects (Gutierrez et al., 2008; Yang, Brown, Liang, Grishin, & Goldstein, 2008).
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Ghrelin is a peptide hormone produced in the gut that is implicated in signaling appetite and regulating dry matter intake (DMI). The objective of this experiment was to determine the change in acyl ghrelin, total ghrelin, and the ghrelin ratio (acyl ghrelin/total ghrelin) over an 84-d DMI and average daily BW gain (ADG) measurement period and to determine the association of those ghrelin measurements with DMI, ADG, ADG:DMI ratio (G:F), and residual feed intake in finishing beef steers and heifers. Blood samples were collected on day 0 and day 83 before feeding and between 0730 h and 1130 h. Samples were analyzed for acyl and total ghrelin using commercially available RIA. DMI in steers was greater during the last 35-d period of the experiment compared with the first 35 d (P < 0.01) and was greater than heifers regardless of period (P < 0.01). Steers had greater acyl ghrelin concentrations on day 0 than heifers, but concentrations decreased by day 83 to equal concentrations in heifers (P < 0.01). Total ghrelin concentrations were lower on day 0 in heifers but increased by day 83 and did not differ from steers on day 83 (P < 0.01). A mixed model analysis was used to determine the association of ghrelin concentrations and ratio with production traits, independent of breed and sire effects. There was an interaction of day 0 acyl ghrelin concentrations with time of sample collection for 84-d DMI (P < 0.01), ADG (P < 0.01), and G:F (P = 0.09), indicating a general positive association of acyl ghrelin with production traits, but the association weakened as time of sample collection increased. The mean ghrelin ratio tended (P = 0.08) to be positively associated with DMI in the last 35-d period. The ghrelin ratio on day 0 interacted with time of sample collection for ADG and G:F (P < 0.05), indicating an overall positive association of the ghrelin ratio with ADG and G:F. Results indicate that ghrelin is associated with DMI, ADG, and feed efficiency of finishing beef cattle, and data lend more evidence that ghrelin is involved in appetite regulation of ad libitum fed cattle.

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ReviewGhrelin, an orexigenic signaling molecule from the gastrointestinal tract

Abstract

Introduction

Section snippets

Structure of ghrelin

Tissue distribution of ghrelin

Growth hormone releasing activity of ghrelin

Appetite-stimulating effect of ghrelin

Regulation of ghrelin secretion

Conclusion

References and recommended reading

Trends Neurosci

J Biol Chem

Biochem Biophys Res Commun

Regul Pept

Peptides

Neurosci Lett

Regul Pept

Biochem Biophys Res Commun

Neurosci Lett

Gastroenterology

Biochem Biophys Res Commun

Central nervous system control of food intake

Nature

Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis

Exp Biol Med

Neuropeptides and appetite control

Diabet Med

Leptin and the regulation of body weight in mammals

Nature

Ghrelin is a growth-hormone-releasing acylated peptide from stomach

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Ghrelin induces adiposity in rodents

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A role for ghrelin in the central regulation of feeding

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Growth hormone secretagogue receptor family members and ligands

Endocrine

Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor

Horm Res

Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans

J Clin Endocrinol Metab

Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

Endocrinology

Ghrelin in neonatal rats: distribution in stomach and its possible role

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The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans

J Clin Endocrinol Metab

Review
Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract