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Ghrelin: An orexigenic and somatotrophic signal from the stomach

Abstract

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is synthesized principally in the stomach and is released in response to fasting. Ghrelin is structurally related to motilin and, together, they represent a novel family of gut–brain regulatory peptides. In addition to having a powerful effect on the secretion of growth hormone, ghrelin stimulates energy production and signals directly to the hypothalamic regulatory nuclei that control energy homeostasis. The study of ghrelin has extended our understanding of how growth is controlled, and has shown that the stomach is an important component of this system.

Key Points

  • The identification of growth hormone secretagogues led to the discovery of a new receptor with homology to the motilin receptor. Subsequent studies led to the identification of its endogenous ligand — ghrelin. Ghrelin can indeed stimulate the release of growth hormone from the pituitary in a way that is independent of the action of growth-hormone-releasing hormone.

  • In addition to its effect on the release of growth hormone, ghrelin is an important regulator of food intake. It is released from the stomach in response to fasting, and increases feeding behaviour by acting on the arcuate nucleus of the hypothalamus.

  • The action of ghrelin is opposite to that of another important regulator of food intake — leptin. Leptin is released from adipose tissue, and its plasma levels decrease in response to fasting. This molecule also acts on the arcuate nucleus of the hypothalamus, where it has an anorexigenic effect.

  • The discovery of ghrelin has several clinical implications. It can be used to stimulate the release of growth hormone in cases of human deficiency, by acting on the endogenous oscillators that control pulsatile hormone release. It can also be used for the regulation of body weight by stimulating food intake, particularly in conditions accompanied by cachexia, such as cancer and AIDS.

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Figure 1: Growth hormone secretagogues.
Figure 2: A new regulatory peptide system — the motilin–ghrelin family.
Figure 3: A simplified model of the action of ghrelin and leptin on feeding-regulatory circuitry.

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Acknowledgements

I sincerely thank M. Kasuga and S. Baba of Kobe University, and M. Nakazato of Miyazaki Medical College, for stimulating discussions. The work was supported by grants from the Japanese Ministry of Education, Science, Sports, and Culture.

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DATABASE LINKS

leptin

insulin

ghrelin

GHS receptor

GH

GHRH

somatostatin

SSTR2

SSTR5

phospholipase C

gastrin

CCK

IGF1

motilin

motilin receptor

NPY

AGRP

MCH

galanin

Fos

Egr1

IL1β

GRP

POMC

CART

MC4 receptor

orexin/hypocretin

Y1

Y5

Y4

PP

Y2

Glossary

SOMATOTROPHS

Cells of the anterior pituitary that are responsible for the production of growth hormone or somatotropin. Somatotroph adenomas cause acromegaly.

HYPOTHALAMIC–HYPOPHYSEAL PORTAL SYSTEM

A system of blood vessels (portal veins) that links the capillaries of the hypothalamus with those of the pituitary.

MOTILIN

A 22-amino-acid peptide produced in the mucosa of the small intestine, which stimulates contractions of the stomach and the release of pepsin.

OXYNTIC MUCOSA

The acid-secreting parietal cells of the gastric mucosa.

ENTEROCHROMAFFIN CELLS

Endocrine cells in the gastric mucosa, which synthesize and secrete histamine in response to stimulation by the hormone gastrin.

PEPTIDE YY

A protein found in the small intestine, which inhibits molecule secretion from the exocrine pancreas.

CIONIN

A molecule from the protochordate Ciona intestinalis that represents the oldest true member of the cholecystokinin/gastrin family.

CERULEIN

A member of the cholecystokinin/gastrin family isolated from the frog Hyla caerulea. It stimulates the secretion of gastric acid in the small intestine of several amphibians.

RESPIRATORY QUOTIENT

The ratio of the volume of CO2 released to the volume of O2 consumed by a body tissue or an organism. The oxidation of carbohydrate results in a respiratory quotient of 1.0, whereas the oxidation of fat results in a quotient of 0.7. So, an increase in the respiratory quotient is sometimes related to increased use of carbohydrate and reduced use of fat to meet specific energy requirements.

AGOUTI-RELATED PEPTIDE

An antagonist of melanocortin receptors that has an important role in the control of food intake. Administration and overexpression of this peptide result in hyperphagia and weight gain.

OREXINS

Peptides associated with feeding behaviour that have also been associated with disturbances of sleep such as narcolepsy.

BOMBESIN

A strong releaser of gastrin and cholecystokinin, which is found in the gut and the brain. It also has a mitogenic action in several cell types.

PANCREATIC POLYPEPTIDE

A molecule, first detected as an impurity present in insulin preparations, which is released after food intake and seems to act as a regulator of pancreatic and gastrointestinal functions.

ACROMEGALY

A disease characterized by the gradual enlargement of the bones of hands, feet, head and chest, and thickening of the skin, lips and vocal chords. It is caused by increased sensitivity to or increased production of growth hormone.

SOMATOPAUSE

A phase in the human lifespan during which the levels of growth hormone are reduced, resulting in the dehydration of cells and organs, and a reduction in their size and function. Somatopause usually begins in people in their mid-forties, but can start earlier.

CACHEXIA

A condition caused by chronic diseases such as cancer, which is characterized by wasting, emaciation, feebleness and inanition.

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Inui, A. Ghrelin: An orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2, 551–560 (2001). https://doi.org/10.1038/35086018

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