Abstract
The endogenous ligand for the growth-hormone (GH) secretagogue receptor was purified from stomach and named ghrelin. It has potent GH-releasing activity and stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin thus plays important roles in maintaining GH release and energy homeostasis in vertebrates. Ghrelin, moreover, stimulates gastric motility and acid secretion, shows positive cardiovascular effects, and has direct actions on bone formation. The diverse functions of ghrelin raise the possibility of its clinical application for GH deficiency, eating disorders, gastrointestinal disease, cardiovascular disease, osteoporosis and aging.
Key Points
-
Ghrelin is a hormone secreted mainly from the stomach into the circulation
-
Ghrelin stimulates growth-hormone release
-
Ghrelin stimulates appetite and increases food intake
-
Ghrelin is useful for treatment of weight loss and eating disorders
-
Gastric bypass decreases ghrelin levels and leads to weight loss
-
Ghrelin improves cardiovascular function
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kojima M et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656–660
Kojima M and Kangawa K (2005) Ghrelin: structure and function. Physiol Rev 85: 495–522
Date Y et al. (2000) 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 141: 4255–4261
Sato T et al. (2005) Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-D-glucose administration. Endocrinology 146: 2510–2516
Cowley MA et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37: 649–661
Howard AD et al. (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273: 974–977
Popovic V et al. (2003) Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level. J Clin Endocrinol Metab 88: 3450–3453
Date Y et al. (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123: 1120–1128
Williams DL et al. (2003) Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology 144: 5184–5187
Hataya Y et al. (2001) A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 86: 4552
Small CJ and Bloom SR (2004) Gut hormones and the control of appetite. Trends Endocrinol Metab 15: 259–263
Nakazato M et al. (2001) A role for ghrelin in the central regulation of feeding. Nature 409: 194–198
Tschop M et al. (2000) Ghrelin induces adiposity in rodents. Nature 407: 908–913
Wren AM et al. (2001) Ghrelin causes hyperphagia and obesity in rats. Diabetes 50: 2540–2547
Chen HY et al. (2004) Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 145: 2607–2612
Hewson AK and Dickson SL (2000) Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J Neuroendocrinol 12: 1047–1049
Wren AM et al. (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86: 5992
Zhang W et al. (2004) Ghrelin stimulates neurogenesis in the dorsal motor nucleus of the vagus. J Physiol 559: 729–737
Date Y et al. (2001) Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem Biophys Res Commun 280: 904–907
le Roux CW et al. (2005) Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. J Clin Endocrinol Metab. 90: 4521–4524
Masuda Y et al. (2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276: 905–908
Nagaya N et al. (2001) Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 280: 1483–1487
Gnanapavan S et al. (2002) The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 87: 2988
Fukushima N et al. (2005) Ghrelin directly regulates bone formation. J Bone Miner Res 20: 790–798
Broglio F et al. (2001) Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 86: 5083–5086
Date Y et al. (2002) Ghrelin is present in pancreatic α-cells of humans and rats and stimulates insulin secretion. Diabetes 51: 124–129
Lee HM et al. (2002) Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 143: 185–190
Reimer MK et al. (2003) Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology 144: 916–921
Hosoda H et al. (2003) Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem 278: 64–70
Sun Y et al. (2003) Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 23: 7973–7981
Wortley KE et al. (2004) Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci USA 101: 8227–8232
De Smet B et al. (2005) Energy homeostasis and gastric emptying in ghrelin knockout mice. J Pharmacol Exp Ther [10.1124/jpet.105.091504]
Cummings DE et al. (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50: 1714–1719
Tschop M et al. (2001) Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest 24: RC19–RC21
Hansen TK et al. (2002) Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol (Oxf) 56: 203–206
Tschop M et al. (2001) Circulating ghrelin levels are decreased in human obesity. Diabetes 50: 707–709
Ariyasu H et al. (2001) Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 86: 4753–4758
Cuntz U et al. (2002) A role for the novel weight-regulating hormone ghrelin in anorexia nervosa. Am Clin Lab 21: 22–23
Otto B et al. (2001) Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 145: 669–673
Cummings DE et al. (2002) Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 346: 1623–1630
Geloneze B et al. (2003) Ghrelin: a gut-brain hormone: effect of gastric bypass surgery. Obes Surg 13: 17–22
Barkan AL et al. (2003) Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J Clin Endocrinol Metab 88: 2180–2184
Norrelund H et al. (2002) Ghrelin immunoreactivity in human plasma is suppressed by somatostatin. Clin Endocrinol (Oxf) 57: 539–546
Qi X et al. (2003) Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion. Exp Biol Med (Maywood) 228: 1028–1032
Takaya K et al. (2000) Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 85: 4908–4911
Choe YH et al. (2005) Increased density of ghrelin expressing cells in the gastric fundus and body in Prader-Willi syndrome. J Clin Endocrinol Metab 90: 5441–5445
Cummings DE et al. (2002) Elevated plasma ghrelin levels in Prader-Willi syndrome. Nat Med 8: 643–644
Muccioli G et al. (2002) Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol 440: 235–254
Troisi A et al. (2005) Plasma ghrelin in anorexia, bulimia, and binge-eating disorder: relations with eating patterns and circulating concentrations of cortisol and thyroid hormones. Neuroendocrinology 81: 259–266
Masuda Y et al. (2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276: 905–908
Depoortere I et al. (2005) Comparison of the gastroprokinetic effects of ghrelin, GHRP-6 and motilin in rats in vivo and in vitro. Eur J Pharmacol 515: 160–168
Sibilia V et al. (2003) Ghrelin protects against ethanol-induced gastric ulcers in rats: studies on the mechanisms of action. Endocrinology 144: 353–359
Baldanzi G et al. (2002) Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 159: 1029–1037
Nagaya N and Kangawa K (2003) Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure. Curr Opin Pharmacol 3: 146–151
Maccarinelli G et al. (2005) Ghrelin regulates proliferation and differentiation of osteoblastic cells. J Endocrinol 184: 249–256
Kim SW et al. (2005) Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells. Bone 37: 359–369
Fukushima N et al. (2005) Ghrelin directly regulates bone formation. J Bone Miner Res 20: 790–798
Hanada T et al. (2003) Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cells. Biochem Biophys Res Commun 301: 275–279
Neary NM et al. (2004) Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 89: 2832–2836
Koutkia P et al. (2004) Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy. Am J Physiol Endocrinol Metab 286: 296–303
Smith RG (2005) Development of growth hormone secretagogues. Endocr Rev 26: 346–360
Acknowledgements
The authors' studies are supported by grants from the Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN), the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) of Japan. We express our gratitude to students, collaborators, and fellow scientists who shared their scientific interests with us and obtained the findings we have reviewed in this article.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Kojima, M., Kangawa, K. Drug Insight: the functions of ghrelin and its potential as a multitherapeutic hormone. Nat Rev Endocrinol 2, 80–88 (2006). https://doi.org/10.1038/ncpendmet0080
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpendmet0080
This article is cited by
-
Common Pathways in Depression and Obesity: The Role of Gut Microbiome and Diets
Current Behavioral Neuroscience Reports (2020)
-
The role of ghrelin in addiction: a review
Psychopharmacology (2014)
-
Effect of Adiponectin and Ghrelin on Apoptosis of Barrett Adenocarcinoma Cell Line
Digestive Diseases and Sciences (2008)
-
Combined estrogen and ghrelin administration restores number of blood vessels and collagen type I/III ratio in the urethral and anal canal submucosa of old ovariectomized rats
International Urogynecology Journal (2008)
-
Characterization of obestatin- and ghrelin-producing cells in the gastrointestinal tract and pancreas of rats: an immunohistochemical and electron-microscopic study
Cell and Tissue Research (2008)