Ghrelin, the peripheral hunger hormone

Figures & data

Figure 1. Human ghrelin gene and its peptide products.

Table I. A summary of the effects of ghrelin (original reports or reviews with further details are indicated in brackets).

Hormonal effects	↑ release of growth hormone in humans and animals 18
	↑ release of adrenocorticotrophin (ACTH) and cortisol in humans and animals 18
	↑ prolactin release in rats and adult humans but ↓ in prepubertal children 19
	↓ secretion of testosterone and luteinizing hormone (LH) 19
	↑ release of anti‐diuretic hormone 20
	↑ secretion of aldosterone in humans 21
Metabolic effects	↑ appetite in animals and humans 18, 22
	regulation of metabolic substrates 18
	↑ gastric emptying and gastrointestinal (GI) tract motility 18
	↓ colonic transit time 23
	stimulates glucose output by hepatocytes 24
	anti‐lipolytic effects on adipose tissue 25
Cardiovascular effects	↑ left ventricular ejection fraction and ↑ cardiac output in humans 18
	↑ stroke volume 18
	↑ systemic vasodilatation and ↓ systemic vascular resistance 18
	↓ blood pressure 18
	↑ coronary perfusion pressure via vasoconstriction of coronary arterioles 26
	reversal of right ventricular hypertrophy and vascular remodelling in pulmonary hypertension 27
	reversal of endothelial dysfunction (the first step in the process of atherosclerosis) 28
Autonomic nervous system effects	↓ sympathetic activity 18
	↓ thermogenesis 18
	possible anti‐emetic effects 28, 29
	↓ release of serotonin 30
Immunological effects	↓ expression of various pro‐inflammatory cytokines, including interleukin (IL)1‐β, IL‐6, and tumour necrosis factor‐α (TNF‐α) 31
	↓ proliferation of anti‐CD3 activated T cells and inhibition of both Th1 and Th2 cytokines in rats and mice 31
	attenuates the known pro‐inflammatory effects of leptin in human neutrophils and T cells 31
	↑ phagocytosis and ↑ superoxide production in trout 32
	may have a renal‐protective effect on kidneys damaged by acute renal failure 33
	exerts protective effects on the gastric mucosa when exposed to stress 130, at least partly mediated by anti‐inflammatory effects 34
	anti‐inflammatory effect in arthritis 35
	improves tissue perfusion in severe sepsis 36
Musculoskeletal system effects	promotes bone formation 116 and ↑ bone mineral density 37
	↓ metabolic activity in chondrocytes 38
	↑ spontaneous locomotor activity in goldfish 39 and may affect locomotor activity in rats 40, 41
Other effects	promotes sleep 18
	↑ anxiety 18
	improves memory and learning 42
	may play a role in embryonic implantation and foetal growth 18
	may have effects on cell proliferation 18

Table II. Transgenic and knockout models for ghrelin and GHS‐R.

Ghrelin	Embryonic/Adult	Finding	Reference
	Embryonic ghrelin knockout (KO)	No detected difference as compared to wild type (WT)	Sun 2003 57
	Embryonic ghrelin KO	KO animals on a high‐fat diet showed preferential use of fat as a metabolic substrate	Wortley 2004 49
	Embryonic ghrelin KO	Males on high‐fat diet showed less weight gain and higher locomotor activity	Wortley 2005 58
	Embryonic ghrelin KO	Young animals showed lower respiratory quotient and higher heat production	De Smet 2006 59
	Adult (given Spiegelmer to neutralize effects of ghrelin)	Weight loss occurred in diet‐induced obese mice	Shearman 2006 60
	Adult (given ghrelin antibody)	Weight loss and reduced food intake in pigs	Vizcarra 2006 61
	Over‐expression of des‐acyl ghrelin in mice	Lower body weight, body length, and GH and insulin‐like growth factor (IGF)‐I levels	Ariyasu 2005 62
	Transgenic over‐expression of ghrelin	Normal size animal. No desensitization of the food intake effect of exogenous ghrelin shown, but lower epididymal fat pad growth response and GH response	Wei 2006 63
	Embryonic ghrelin/leptin double KO	Obesity and hyperphagia shown, but with improved insulin sensitivity	Sun 2006 64
GHS‐R	Embryonic/Adult	Finding	Reference
	Embryonic GHS‐R KO	Lower IGF‐I and body weight	Sun 2004 13
	Embryonic GHS‐R KO	Reduced food intake and weight gain on high‐fat diet, increased fat burning	Zigman 2005 15
	Adult (given GHS‐R antagonist (D‐Lys‐3)‐GHRP‐6)	Reduced food intake in lean, diet‐induced‐obesity and ob/ob mice, and reduced weight gain in ob/ob mice	Asakawa 2003 65
	Embryonic (given antisense GHS‐R mRNA, which selectively attenuates GHS‐R protein expression in the arcuate nucleus)	Lower body weight and less adipose tissue, reduced food intake, and abolition of the stimulatory effect of GHS on feeding	Shuto 2002 66

GHS‐R = growth hormone secretagogue receptor.

Figure 2. Ghrelin reaches the hypothalamus via three different pathways18.

Table III. Summary of the findings of studies published between January 2005 and July 2006 with reference to the subject of bariatric surgery and its effects on ghrelin levels. (For previous studies, refer to 205).

Increased ghrelin levels		Reduced ghrelin levels		Ghrelin levels unaffected		Biphasic ghrelin levels
Procedure	Reference	Procedure	Reference	Procedure	Reference	Procedure	Reference
LAGB	208	sleeve gastrectomy	208	RYGB	213	RYGB	206
VGB	209	RYGB	210	RYGB	214	RYGB	207
		RYGB	211	GB	214
		RYGB	212	RYGB	215
				LAGB	216
				VGB	212

RYGB = Roux‐en‐Y gastric bypass; VGB = Vertical gastric banding; LAGB = laparoscopic adjustable gastric banding.

Korbonits M., Goldstone A. P., Gueorguiev M., Grossman A. B. Ghrelin—a hormone with multiple functions. Front Neuroendocrinol 2004; 25: 27–68

 PubMed Web of Science ®Google Scholar

Tena‐Sempere M. Exploring the role of ghrelin as novel regulator of gonadal function. Growth Horm IGF Res 2005; 15: 83–8

 Google Scholar

Hosoda H., Kojima M., Kangawa K. Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 2006; 100: 398–410

 PubMed Web of Science ®Google Scholar

Arvat E., Maccario M., Di Vito L., Broglio F., Benso A., Gottero C., et al. Endocrine activities of ghrelin, a natural GH secretagogue, in humans: comparison and interactions with hexarelin, a non natural peptidyl GHS, and GH‐releasing hormone. J Clin Endocrinol Metab 2001; 86: 1169–74

 PubMed Web of Science ®Google Scholar

Tschöp M., Smiley D. L., Heiman M. L. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908–13

 PubMed Web of Science ®Google Scholar

Tebbe J. J., Mronga S., Tebbe C. G., Ortmann E., Arnold R., Schafer M. K. Ghrelin‐induced stimulation of colonic propulsion is dependent on hypothalamic neuropeptide Y1‐ and corticotrophin‐releasing factor 1 receptor activation. J Neuroendocrinol 2005; 17: 570–6

 PubMedGoogle Scholar

Gauna C., Delhanty P. J., Hofland L. J., Janssen J. A., Broglio F., Ross R. J., et al. Ghrelin stimulates, whereas des‐octanoyl ghrelin inhibits, glucose output by primary hepatocytes. J Clin Endocrinol Metab 2005; 90: 1055–60

 PubMed Web of Science ®Google Scholar

Muccioli G., Pons N., Ghe C., Catapano F., Granata R., Ghigo E. Ghrelin and des‐acyl ghrelin both inhibit isoproterenol‐induced lipolysis in rat adipocytes via a non‐type 1a growth hormone secretagogue receptor. Eur J Pharmacol 2004; 498: 27–35

 PubMed Web of Science ®Google Scholar

Cao J. M., Ong H., Chen C. Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab 2006; 17: 13–18

 PubMedGoogle Scholar

Henriques‐Coelho T., Roncon‐Albuquerque J. R., Lourenco A. P., Baptista M. J., Oliveira S. M., Brandao‐Nogueira A., et al. Ghrelin reverses molecular, structural and hemodynamic alterations of the right ventricle in pulmonary hypertension. Rev Port Cardiol 2006; 25: 55–63

 PubMedGoogle Scholar

Tesauro M., Schinzari F., Iantorno M., Rizza S., Melina D., Lauro D., et al. Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation 2005; 112: 2986–92

 PubMed Web of Science ®Google Scholar

Rudd J. A., Ngan M. P., Wai M. K., King A. G., Witherington J., Andrews P. L., et al. Anti‐emetic activity of ghrelin in ferrets exposed to the cytotoxic anti‐cancer agent cisplatin. Neurosci Lett 2006; 392: 79–83

 PubMed Web of Science ®Google Scholar

Brunetti L., Recinella L., Orlando G., Michelotto B., Di Nisio C., Vacca M. Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release in the hypothalamus. Eur J Pharmacol 2002; 454: 189–92

 Google Scholar

Dixit V. D., Taub D. D. Ghrelin and immunity: A young player in an old field. Exp Gerontol 2005; 40: 900–10

 PubMed Web of Science ®Google Scholar

Yada T., Kaiya H., Mutoh K., Azuma T., Hyodo S., Kangawa K. Ghrelin stimulates phagocytosis and superoxide production in fish leukocytes. J Endocrinol 2006; 189: 57–65

 Google Scholar

Takeda R., Nishimatsu H., Suzuki E., Satonaka H., Nagata D., Oba S., et al. Ghrelin improves renal function in mice with ischemic acute renal failure. J Am Soc Nephrol 2006; 17: 113–21

 PubMed Web of Science ®Google Scholar

Halem H. A., Taylor J. E., Dong J. Z., Shen Y., Datta R., Abizaid A., et al. A novel growth hormone secretagogue‐1a receptor antagonist that blocks ghrelin‐induced growth hormone secretion but induces increased body weight gain. Neuroendocrinol 2005; 81: 339–49

 PubMed Web of Science ®Google Scholar

Konturek P. C., Brzozowski T., Pajdo R., Nikiforuk A., Kwiecien S., Harsch I., et al. Ghrelin‐a new gastroprotective factor in gastric mucosa. J Physiol Pharmacol 2004; 55: 325–36

 PubMed Web of Science ®Google Scholar

Granado M., Priego T., Martin A. I., Villanua M. A., Lopez‐Calderon A. Anti‐inflammatory effect of the ghrelin agonist growth hormone‐releasing peptide‐2 (GHRP‐2) in arthritic rats. Am J Physiol Endocrinol Metab 2005; 288: E486–92

 Web of Science ®Google Scholar

Wu R., Dong W., Zhou M., Cui X., Hank S. H., Wang P. Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin‐1. Cardiovasc Res 2005; 68: 318–26

 PubMed Web of Science ®Google Scholar

Heijboer A. C., van den Hoek A. M., Parlevliet E. T., Havekes L. M., Romijn J. A., Pijl H., et al. Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice. Diabetologia 2006; 49: 732–8

 PubMed Web of Science ®Google Scholar

Fukushima N., Hanada R., Teranishi H., Fukue Y., Tachibana T., Ishikawa H., et al. Ghrelin directly regulates bone formation. J Bone Miner Res 2005; 20: 790–8

 PubMed Web of Science ®Google Scholar

Caminos J. E., Gualillo O., Lago F., Otero M., Blanco M., Gallego R., et al. The endogenous growth hormone secretagogue (ghrelin) is synthesized and secreted by chondrocytes. Endocrinology 2005; 146: 1285–92

 PubMedGoogle Scholar

Matsuda K., Miura T., Kaiya H., Maruyama K., Uchiyama M., Kangawa K., et al. Stimulatory effect of n‐octanoylated ghrelin on locomotor activity in the goldfish, Carassius auratus. Peptides 2006; 27: 1335–40

 Google Scholar

Jaszberenyi M., Bujdoso E., Bagosi Z., Telegdy G. Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin. Horm Behav 2006; 50: 266–73

 PubMedGoogle Scholar

Tang‐Christensen M., Vrang N., Ortmann S., Bidlingmaier M., Horvath T. L., Tschop M. Central Administration of Ghrelin and Agouti‐Related Protein (83‐132) Increases Food Intake and Decreases Spontaneous Locomotor Activity in Rats. Endocrinology 2004; 145: 4645–52

 PubMed Web of Science ®Google Scholar

Diano S., Farr S. A., Benoit S. C., McNay E. C., da Silva I., Horvath B., et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006; 9: 381–8

 PubMed Web of Science ®Google Scholar

Sun Y., Ahmed S., Smith R. G. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003; 23: 7973–81

 PubMed Web of Science ®Google Scholar

Wortley K. E., Anderson K. D., Garcia K., Murray J. D., Malinova L., Liu R., et al. Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci USA 2004; 101: 8227–32

 PubMed Web of Science ®Google Scholar

Wortley K. E., Del Rincon J. P., Murray J. D., Garcia K., Iida K., Thorner M. O., et al. Absence of ghrelin protects against early‐onset obesity. J Clin Invest 2005; 115: 3573–8

 PubMed Web of Science ®Google Scholar

De Smet B., Depoortere I., Moechars D., Swennen Q., Moreaux B., Cryns K., et al. Energy homeostasis and gastric emptying in ghrelin knockout mice. J Pharmacol Exp Ther 2006; 316: 431–9

 PubMed Web of Science ®Google Scholar

Shearman L. P., Wang S. P., Helmling S., Stribling D. S., Mazur P., Ge L., et al. Ghrelin neutralization by a ribonucleic acid‐SPM ameliorates obesity in diet‐induced obese mice. Endocrinology 2006; 147: 1517–26

 PubMed Web of Science ®Google Scholar

Vizcarra J. A., Kirby J. D., Kim S. K., Galyean M. L. Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs. Domest Anim Endocrinol 2006 Jun 8, [Epub ahead of print]

 Google Scholar

Ariyasu H., Takaya K., Iwakura H., Hosoda H., Akamizu T., Arai Y., et al. Transgenic mice overexpressing des‐acyl ghrelin show small phenotype. Endocrinology 2005; 146: 355–64

 Google Scholar

Wei W., Qi X., Reed J., Ceci J., Wang H. Q., Wang G., et al. Effect of chronic hyperghrelinemia on ingestive action of ghrelin. Amer J Physiol Regul Integr Comp Physiol 2006; 290: R803–08

 Google Scholar

Sun Y., Asnicar M., Saha P. K., Chan L., Smith R. G. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab 2006; 3: 379–86

 PubMed Web of Science ®Google Scholar

Sun Y., Wang P., Zheng H., Smith R. G. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 2004; 101: 4679–84

 PubMed Web of Science ®Google Scholar

Zigman J. M., Jones J. E., Lee C. E., Saper C. B., Elmquist J. K. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 2006; 494: 528–48

 PubMed Web of Science ®Google Scholar

Asakawa A., Inui A., Kaga T., Katsuura G., Fujimiya M., Fujino M. A., et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 2003; 52: 947–52

 PubMed Web of Science ®Google Scholar

Shuto Y., Shibasaki T., Otagiri A., Kuriyama H., Ohata H., Tamura H., et al. Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 2002; 109: 1429–36

 PubMed Web of Science ®Google Scholar

Aylwin S. J. Gastrointestinal surgery and gut hormones. Current Opinion In Endocrinology and Diabetes 2005; 12: 89–98

 Google Scholar

Langer F. B., Reza Hoda M. A., Bohdjalian A., Felberbauer F. X., Zacherl J., Wenzl E., et al. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. Obes Surg 2005; 15: 1024–9

 PubMed Web of Science ®Google Scholar

Borg C. M., Le Roux C. W., Ghatei M. A., Bloom S. R., Patel A. G., Aylwin S. J. Progressive rise in gut hormone levels after Roux‐en‐Y gastric bypass suggests gut adaptation and explains altered satiety. Br J Surg 2006; 93: 210–15

 PubMed Web of Science ®Google Scholar

Mariani L. M., Fusco A., Turriziani M., Veneziani A., Marini M. A., de Lorenzo A., et al. Transient increase of plasma ghrelin after laparoscopic adjustable gastric banding in morbid obesity. Horm Metab Res 2005; 37: 242–5

 PubMed Web of Science ®Google Scholar

Foschi D., Corsi F., Rizzi A., Asti E., Carsenzuola V., Vago T., et al. Vertical banded gastroplasty modifies plasma ghrelin secretion in obese patients. Obes Surg 2005; 15: 1129–32

 PubMed Web of Science ®Google Scholar

Suzuki S., Ramos E. J., Goncalves C. G., Chen C., Meguid M. M. Changes in GI hormones and their effect on gastric emptying and transit times after Roux‐en‐Y gastric bypass in rat model. Surgery 2005; 138: 283–90

 PubMed Web of Science ®Google Scholar

Le Roux C. W., Aylwin S. J., Batterham R. L., Borg C. M., Coyle F., Prasad V., et al. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 2006; 243: 108–14

 PubMed Web of Science ®Google Scholar

Stratis C., Alexandrides T., Vagenas K., Kalfarentzos F. Ghrelin and peptide YY levels after a variant of biliopancreatic diversion with Roux‐en‐Y gastric bypass versus after colectomy: a prospective comparative study. Obes Surg 2006; 16: 752–8

 PubMed Web of Science ®Google Scholar

Stylopoulos N., Davis P., Pettit J. D., Rattner D. W., Kaplan L. M. Changes in serum ghrelin predict weight loss after Roux‐en‐Y gastric bypass in rats. Surg Endosc 2005; 19: 942–6

 Google Scholar

Lin E., Gletsu N., Fugate K., McClusky D., Gu L. H., Zhu J. L., et al. The effects of gastric surgery on systemic ghrelin levels in the morbidly obese. Arch Surg 2004; 139: 780–4

 PubMedGoogle Scholar

Korner J., Bessler M., Cirilo L. J., Conwell I. M., Daud A., Restuccia N. L., et al. Effects of Roux‐en‐Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin. J Clin Endocrinol Metab 2005; 90: 359–65

 PubMed Web of Science ®Google Scholar

Ram E., Vishne T., Diker D., Gal‐Ad I., Maayan R., Lerner I., et al. Impact of gastric banding on plasma ghrelin, growth hormone, cortisol, DHEA and DHEA‐S levels. Obes Surg 2005; 15: 1118–23

 Google Scholar