- Rodger A Liddle, MD
Rodger A Liddle, MD
- Professor of Medicine
- Duke University Medical School
Ghrelin is a 28 amino acid peptide that is the natural ligand for the growth hormone secretagogue (GHS) receptor [1,2]. Based on its structure, it is a member of the motilin family of peptides. When administered peripherally or into the central nervous system, ghrelin stimulates secretion of growth hormone, increases food intake, and produces weight gain [3,4].
Ghrelin, which is produced by the stomach, increases during periods of fasting or under conditions associated with negative energy balance such as starvation or anorexia. In contrast, ghrelin levels are low after eating or with hyperglycemia, and in obesity. Accumulating evidence indicates that ghrelin plays a central role in the neurohormonal regulation of food intake and energy homeostasis.
This topic review will provide an overview on the biology of ghrelin. Related subjects are discussed separately. (See "Pathogenesis of obesity" and "Physiology of leptin" and "Obesity in adults: Drug therapy".)
Ghrelin was discovered in 1999 when it was noted that tissue extracts from the rat stomach activated the GHS receptor . It has since been recognized that the stomach is the richest source of ghrelin. Over 90 percent of the body's ghrelin is in the stomach and duodenum. Lower amounts are found in the pancreas, pituitary, kidney, and placenta. A limited region of the arcuate nucleus of the hypothalamus contains small amounts of ghrelin.
Ghrelin is most abundant in the gastric fundus where it is produced in oxyntic glands by distinctive endocrine cells known as P/D1 cells [5,6]. Ghrelin-containing cells are of two types:
- Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402:656.
- Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin--a hormone with multiple functions. Front Neuroendocrinol 2004; 25:27.
- Takaya K, Ariyasu H, Kanamoto N, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000; 85:4908.
- Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409:194.
- Ariyasu H, Takaya K, Tagami T, et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 2001; 86:4753.
- Date Y, Kojima M, Hosoda H, et al. 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 2000; 141:4255.
- Hosoda H, Kojima M, Kangawa K. Ghrelin and the regulation of food intake and energy balance. Mol Interv 2002; 2:494.
- Zhang JV, Ren PG, Avsian-Kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 2005; 310:996.
- Granata R, Baragli A, Settanni F, et al. Unraveling the role of the ghrelin gene peptides in the endocrine pancreas. J Mol Endocrinol 2010; 45:107.
- Seim I, Walpole C, Amorim L, et al. The expanding roles of the ghrelin-gene derived peptide obestatin in health and disease. Mol Cell Endocrinol 2011; 340:111.
- Markowska A, Ziółkowska A, Jaszczyńska-Nowinka K, et al. Elevated blood plasma concentrations of active ghrelin and obestatin in benign ovarian neoplasms and ovarian cancers. Eur J Gynaecol Oncol 2009; 30:518.
- Muccioli G, Baragli A, Granata R, et al. Heterogeneity of ghrelin/growth hormone secretagogue receptors. Toward the understanding of the molecular identity of novel ghrelin/GHS receptors. Neuroendocrinology 2007; 86:147.
- Mundinger TO, Cummings DE, Taborsky GJ Jr. Direct stimulation of ghrelin secretion by sympathetic nerves. Endocrinology 2006; 147:2893.
- Drazen DL, Vahl TP, D'Alessio DA, et al. Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology 2006; 147:23.
- Cummings DE, Foster-Schubert KE, Overduin J. Ghrelin and energy balance: focus on current controversies. Curr Drug Targets 2005; 6:153.
- Papotti M, Cassoni P, Volante M, et al. Ghrelin-producing endocrine tumors of the stomach and intestine. J Clin Endocrinol Metab 2001; 86:5052.
- Tschöp M, Weyer C, Tataranni PA, et al. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50:707.
- Tschöp M, Wawarta R, Riepl RL, et al. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest 2001; 24:RC19.
- Otto B, Cuntz U, Fruehauf E, et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001; 145:669.
- Checchi S, Montanaro A, Pasqui L, et al. Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies. J Clin Endocrinol Metab 2007; 92:4346.
- Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346:1623.
- Hataya Y, Akamizu T, Takaya K, et al. A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 2001; 86:4552.
- Date Y, Murakami N, Toshinai K, et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 2002; 123:1120.
- Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest 2007; 117:13.
- le Roux CW, Patterson M, Vincent RP, et al. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab 2005; 90:1068.
- Wells T. Ghrelin - Defender of fat. Prog Lipid Res 2009; 48:257.
- Kamegai J, Tamura H, Shimizu T, et al. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 2001; 50:2438.
- Granado M, Priego T, Martín AI, et al. 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.
- Dixit VD, Schaffer EM, Pyle RS, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 2004; 114:57.
- Fukushima N, Hanada R, Teranishi H, et al. Ghrelin directly regulates bone formation. J Bone Miner Res 2005; 20:790.
- Misra M, Miller KK, Stewart V, et al. Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents. J Clin Endocrinol Metab 2005; 90:5082.
- Inui A, Asakawa A, Bowers CY, et al. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 2004; 18:439.
- Anderson B, Switzer NJ, Almamar A, et al. The impact of laparoscopic sleeve gastrectomy on plasma ghrelin levels: a systematic review. Obes Surg 2013; 23:1476.
- Thaler JP, Cummings DE. Minireview: Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology 2009; 150:2518.
- Nicholls RD, Knepper JL. Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet 2001; 2:153.
- Cummings DE, Clement K, Purnell JQ, et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med 2002; 8:643.
- DelParigi A, Tschöp M, Heiman ML, et al. High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome. J Clin Endocrinol Metab 2002; 87:5461.
- Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86:5992.
- Rittmaster RS, Loriaux DL, Merriam GR. Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion. Neuroendocrinology 1987; 45:118.
- van der Lely AJ, Tschöp M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004; 25:426.
- Akamizu T, Kangawa K. Ghrelin for cachexia. J Cachexia Sarcopenia Muscle 2010; 1:169.
- Jeffery P, McDonald V, Tippett E, McGuckin M. Ghrelin in gastrointestinal disease. Mol Cell Endocrinol 2011; 340:35.
- Camilleri M, Acosta A. A ghrelin agonist fails to show benefit in patients with diabetic gastroparesis: let's not throw the baby out with the bath water. Neurogastroenterol Motil 2013; 25:859.
- TISSUE DISTRIBUTION
- Effects of ghrelin on food intake and energy balance
- - Adiposity
- - Neuropeptide Y
- Effect of ghrelin on gastric motility
- Effect of ghrelin on immune function
- Effect of ghrelin on bone formation
- CLINICAL CONDITIONS AND APPLICATION
- Gastric bypass surgery
- Prader-Willi syndrome