Ghrelin // is a 28-amino acid hunger-stimulating peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas. Ghrelin together with obestatin is produced from cleavage of the ghrelin/obestatin prepropeptide (also known as the appetite-regulating hormone or growth hormone secretagogue or motilin-related peptide), which in turn is encoded by the GHRL gene. The full-length preproghrelin is homologous to the promotilin protein classified in the motilin family, and is cleaved into the following two chains: (1) Ghrelin and (2) Obestatin. Ghrelin receptors are expressed in a wide variety of tissues, including the pituitary, stomach, intestine, pancreas, thymus, gonads, thyroid, and heart. The diversity of ghrelin receptor locations suggests ghrelin has diverse biological functions.
Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.
Ghrelin is a potent stimulator of growth hormone secretion from the anterior pituitary gland. The ghrelin receptor is a G protein-coupled receptor, known as the growth hormone secretagogue receptor. Ghrelin binds to the GHSR1a splice-variant of this receptor, which is present in high density in the hypothalamus and pituitary as well as vagal afferent cell bodies and vagal afferent endings throughout the gastro-intestinal tract.
Ghrelin plays a significant role in neurotrophy, in particular in the hippocampus, and is essential for cognitive adaptation to changing environments and the process of learning. Ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.
- 1 History and name
- 2 Synthesis and variants
- 3 Mechanism of action
- 4 Function
- 5 Clinical significance
- 6 See also
- 7 References
- 8 Further reading
- 9 External links
History and name
The discovery of ghrelin followed after the discovery of the growth hormone secretagogue type 1A receptor in 1996 and was reported by Masayasu Kojima and colleagues in 1999. The name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root ghre, meaning to grow. (Growth Hormone Release-Inducing = Ghrelin)
Synthesis and variants
The mRNA from the GHRL gene codes for a 117-amino acid peptide called preproghrelin, containing 4 exons. The signalling peptide molecule of this larger precursor is cleaved to produce proghrelin. Proghrelin is cleaved in two to produce the 28-amino acid peptide ghrelin (unacylated) and C-ghrelin (of which obestatin is presumed to be a cleaved form).
'Ghrelin' usually refers to the octanoylated form of ghrelin (acyl ghrelin). This is the 28-amino acid peptide sequence with an octanoylation on the third amino acid (serine). The octanoylation is performed by the ghrelin O-acyltransferase (GOAT) protein (a member of the membrane-bound O-acyltransferase family of proteins), located in the stomach and pancreas. This peptide can activate the GHSR receptor and is, thus, known as the active form of ghrelin. The non-octanoylated form is known as desacyl ghrelin or the inactive form, and does not activate GHSR1a and, thus, does not release growth hormone like acyl ghrelin; however, studies have shown it has its own effects. Side-chains other than octanoyl have also been observed.
Mechanism of action
Ghrelin has emerged as the first identified circulating hunger hormone. Ghrelin is also the only known circulating orexigen, or appetite-enhancing hormone. It is produced mainly in the stomach and the first part of the small intestine (duodenum), but can also be secreted by the jejunum, lungs, pancreatic islets, gonads, adrenal cortex, placenta, kidney, and brain. The diversity in areas of ghrelin production indicates that this hormone has widespread and numerous biological functions. Ghrelin and synthetic ghrelin mimetics (the growth hormone secretagogues) increase food intake and increase fat mass by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus that include the orexigenic neuropeptide Y (NPY) neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as ethanol. Indeed, central ghrelin signalling is required for reward from alcohol and palatable/rewarding foods. There is also strong evidence that ghrelin has a peripheral appetite modulatory effect on satiety by affecting the mechanosensitivity of gastric vagal afferents, making them less sensitive to distension resulting in overeating.
Relation to obestatin
Obestatin is a putative hormone that was described, in late 2005, to decrease appetite. Both obestatin and ghrelin are encoded by the same gene; the gene's product breaks apart to yield the two peptide hormones. The physiological value of this mechanism is unknown, and it should be noted that no secretory convertase is capable of cleaving the recombinant precursor by cleavage at the single basic residue required for generation of obestatin; thus, the physiological generation of this peptide is questionable.
Ghrelin has been linked to inducing appetite and feeding behaviors. Circulating ghrelin levels are the highest right before a meal and the lowest right after. Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner. So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number. Ghrelin injections also increase an animal's motivation to seek out food, behaviors including increased sniffing, foraging for food, and hoarding food. Ghrelin also readies the body for the incoming nutrients by stimulating gastrointestinal motility and gastric acid secretions.
An anti-obesity vaccine that is directed against the hormone ghrelin in rodents and pigs has been developed. The vaccine uses the immune system, to be specific antibodies, to bind to selected targets, directing the body's own immune response against them. This prevents ghrelin from reaching the central nervous system, thus producing a desired reduction in weight gain.
Body weight regulation
Body weight is regulated through energy balance, the amount of energy taken in versus the amount of energy expended over an extended period of time. Studies have shown that ghrelin levels are negatively correlated with weight. This data suggests that ghrelin functions as an adiposity signal, a messenger between the body's energy stores and the brain. When a person loses weight their ghrelin levels increase, which causes increased food consumption and weight gain. On the other hand, when a person gains weight, ghrelin levels drop, leading to a decrease in food consumption and weight loss (Tung, 2005). This suggests that ghrelin acts as a body weight regulator, continuously keeping one's body weight and energy stores in check.
Ghrelin has been proposed as a hormone that promotes intestinal cell proliferation and inhibits its apoptosis during inflammatory states and oxidative stress. It also suppresses the pro-inflammatory mechanisms and augments anti-inflammatory mechanisms, thus creating a possibility of its therapeutic use in various gastrointestinal inflammatory conditions, including colitis, ischemia reperfusion injury, and sepsis. In fact, animal models of colitis, ischemia reperfusion, and sepsis-related gut dysfunction have been shown to benefit from therapeutic doses of ghrelin. It has also been shown to have regenerative capacity and is beneficial in case of mucosal injury to the stomach. Ghrelin also enhances the motility of the gastrointestinal tract, as does motilin. Ghrelin also appears to promote gastrointestinal and pancreatic malignancy.
Learning and memory
Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, altering nerve-cell connections, and so altering learning and memory. It is suggested that learning may be best during the day and when the stomach is empty, since ghrelin levels are higher at these times. A similar effect for human neural-physiology is possible. In rodents, X/A-like cells produce ghrelin.
Ghrelin knock-out mice (who never express ghrelin) have increased anxiety in response to a variety of stressors, such as acute restraint stress and social stress in an experimental settings. In normal mice, ghrelin can stimulate the Hypothalamic-pituitary-adrenal axis, from the anterior pituitary.
Ghrelin has been shown to have implications for depression prevention. Antidepressant-like attributes were demonstrated when mice with high levels of ghrelin and mice with the ghrelin gene knocked out underwent social defeat stress and then were placed in the forced swim tank. Mice with elevated ghrelin swam more than ghrelin deficient mice. These ghrelin-deficient mice exhibited more social avoidance as well. These mice did not exhibit depression-like behaviors when injected with a commonly prescribed antidepressant, suggesting that ghrelin acts as a short-term natural adaptation against depression.
Short sleep duration is associated with high levels of ghrelin and obesity. An inverse relationship between the hours of sleep and blood plasma concentrations of ghrelin exists; as the hours of sleep increase, ghrelin concentrations lower, thereby potentially reducing appetite and avoiding potential obesity.
Role in stress-induced anxiety disorders
Prior stress exposure heightens fear learning during Pavlovian fear conditioning. Stress-related increases in ghrelin circulation were shown to be necessary and sufficient for stress to increase fear learning. Ghrelin was found to be upregulated by stress even in the absence of adrenal hormones. Blocking the ghrelin receptor during stress abolished stress-related enhancement of fear memory without blunting other markers of stress. These results suggest that ghrelin is a novel branch of the stress response. Human studies are needed to translate the use of anti-ghrelin treatments to prevent stress-induced psychiatric disorders.
Regarding the reproductive system, ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus, thus appearing to potentially cause decreased fertility.
Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals, suggesting that ghrelin does not contribute to obesity, except in the cases of Prader-Willi syndrome-induced obesity, where high ghrelin levels are correlated with increased food intake. Those suffering from the eating disorder anorexia nervosa have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls. One small single-blind study found that intravenous administration of ghrelin to anorexia nervosa patients increased food intake by 12–36% over the trial period.
The level of ghrelin increases during the time of day from midnight to dawn in thinner people, which suggests there is a flaw in the circadian system of obese individuals. Short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces ghrelin, which stimulates appetite and creates less leptin, which, among its many other effects, suppresses appetite.
At least one study found that gastric bypass surgery not only reduces the gut's capacity for food but also dramatically lowers ghrelin levels compared to both lean controls and those that lost weight through dieting alone. However, studies are conflicting as to whether or not ghrelin levels return to close to normal with gastric bypass patients in the long term after weight loss has stabilized. Bariatric surgeries involving vertical sleeve gastrectomy reduce plasma ghrelin levels by about 60% in the long term.
Ghrelin, through its receptor increases the concentration of dopamine in the substantia nigra, a region of the brain where dopamine cell degeneration leads to Parkinson's disease. Hence, ghrelin may find application in slowing down the onset of Parkinson's disease.
- Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M (2004). "Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ". FASEB J. 18 (3): 439–56. doi:10.1096/fj.03-0641rev. PMID 15003990.
- Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (August 1996). "A receptor in pituitary and hypothalamus that functions in growth hormone release". Science 273 (5277): 974–7. Bibcode:1996Sci...273..974H. doi:10.1126/science.273.5277.974. PMID 8688086.
- Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (May 2002). "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery". N. Engl. J. Med. 346 (21): 1623–30. doi:10.1056/NEJMoa012908. PMID 12023994.
- Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999). "Ghrelin is a growth-hormone-releasing acylated peptide from stomach". Nature 402 (6762): 656–60. Bibcode:1999Natur.402..656K. doi:10.1038/45230. PMID 10604470.
- Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH (2010). "Ghrelin in the regulation of body weight and metabolism". Front Neuroendocrinol. 31 (1): 44–60. doi:10.1016/j.yfrne.2009.10.008. PMID 19896496.
- Page A, Slattery J, Milte C, Laker R, O'Donnell T, Dorian C, Brierley S, Blackshaw LA (2007). "Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents". Am J Physiol Gastrointest Liver Physiol. 292 (5): 1376–1384. doi:10.1152/ajpgi.00536.2006. PMID 17290011.
- Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschöp MH, Horvath TL (March 2006). "Ghrelin controls hippocampal spine synapse density and memory performance". Nat. Neurosci. 9 (3): 381–8. doi:10.1038/nn1656. PMID 16491079. Lay summary – Science Blog.
- Atcha Z, Chen WS, Ong AB, Wong FK, Neo A, Browne ER, Witherington J, Pemberton DJ (2009). "Cognitive enhancing effects of ghrelin receptor agonists". Psychopharmacology (Berl). 206 (3): 415–27. doi:10.1007/s00213-009-1620-6. PMID 19652956.
- Xu X, Jhun BS, Ha CH, Jin ZG (2008). "Molecular Mechanisms of Ghrelin-Mediated Endothelial Nitric Oxide Synthase Activation". Endocrinology. 149 (8): 4183–4192. doi:10.1210/en.2008-0255. PMC 2488251. PMID 18450953.
- Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M (March 2004). "Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ". FASEB J. 18 (3): 439–56. doi:10.1096/fj.03-0641rev. PMID 15003990.
- Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghé C, Deghenghi R, Ghigo E, Muccioli G (2003). "Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin". Eur J Pharmacol. 476 (1–2): 87–95. doi:10.1016/S0014-2999(03)02083-1. PMID 12969753.
- Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, Van Der Lely AJ, Ghigo E (2004). "Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans". J Clin Endocrinol Metab. 89 (6): 3062–5. doi:10.1210/jc.2003-031964. PMID 15181099.
- Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Murakami N, Miyazato M, Kangawa K, Nakazato M (2006). "Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor". Endocrinology. 147 (5): 2306–14. doi:10.1210/en.2005-1357. PMID 16484324.
- Gauna C, Delhanty PJ, Hofland LJ, Janssen JA, Broglio F, Ross RJ, Ghigo E, van der Lely AJ (2005). "Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes". J Clin Endocrinol Metab. 90 (2): 1055–6. doi:10.1210/jc.2004-1069. PMID 15536157.
- Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB (2004). "Ghrelin—a hormone with multiple functions". Front Neuroendocrinol. 25 (1): 27–68. doi:10.1016/j.yfrne.2004.03.002. PMID 15183037.
- Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K (October 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 (10): 4753–8. doi:10.1210/jcem.86.10.7885. PMID 11600536.
- Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL (2001). "Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues". Biochem Biophys Res Commun 280 (1): 132–138. doi:10.1006/bbrc.2000.4065. PMID 11162489.
- Tschöp M, Smiley DL, Heiman ML (2000). "Ghrelin induces adiposity in rodents". Nature 407 (6806): 908–913. doi:10.1038/35038090. PMID 11057670.
- Hewson AK, 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 (11): 1047–1049. doi:10.1046/j.1365-2826.2000.00584.x. PMID 11069119.
- Dickson SL, Leng G, Robinson ICAF (1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience 54 (2): 303–306. doi:10.1016/0306-4522(93)90197-N. PMID 8492908.
- Dickson SL, Luckman SM (1997). "Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6". Endocrinology. 138 (2): 771–777. doi:10.1210/en.138.2.771. PMID 9003014.
- Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL (2002). "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes. 51 (12): 3412–3419. doi:10.2337/diabetes.51.12.3412. PMID 12453894.
- Jerlhag E, Egecioglu, E, Dickson SL, Andersson M, Svensson L, Engel JA (2004). "Ghrelin Stimulates Locomotor Activity and Accumbal Dopamine-Overflow via Central Cholinergic Systems in Mice: Implications for its Involvement in Brain Reward". Addiction Biology 11 (1): 45–54. doi:10.1111/j.1369-1600.2006.00002.x. PMID 16759336.
- Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA (2007). "Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens". Addiction Biology 12 (1): 6–16. doi:10.1111/j.1369-1600.2006.00041.x. PMID 17407492.
- Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA (July 2009). "Requirement of central ghrelin signaling for alcohol reward". Proc. Natl. Acad. Sci. U.S.A. 106 (27): 11318–23. Bibcode:2009PNAS..10611318J. doi:10.1073/pnas.0812809106. PMC 2703665. PMID 19564604.
- Egecioglu E, Jerlhag E, Salomé N, Skibicka KP, Haage D, Bohlooly-Y M, Andersson D, Bjursell M, Perrissoud D, Engel JA, Dickson SL (July 2010). "Ghrelin increases intake of rewarding food in rodents". Addict Biol 15 (3): 304–11. doi:10.1111/j.1369-1600.2010.00216.x. PMC 2901520. PMID 20477752.
- Skibicka KP, Hansson C, Egecioglu E, Dickson SL (January 2012). "Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression". Addict Biol 17 (1): 95–107. doi:10.1111/j.1369-1600.2010.00294.x. PMC 3298643. PMID 21309956.
- Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ (November 2005). "Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake". Science 310 (5750): 996–9. Bibcode:2005Sci...310..996Z. doi:10.1126/science.1117255. PMID 16284174.
- Ozawa A, Cai Y, Lindberg I (April 2007). "Production of Bioactive Peptides in an In Vitro System". Anal Biochem 366 (2): 182–9. doi:10.1016/j.ab.2007.04.020. PMC 2128726. PMID 17540328.
- Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D (August 2004). "Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues". Am. J. Physiol. Endocrinol. Metab. 287 (2): E297–304. doi:10.1152/ajpendo.00582.2003. PMID 15039149.
- Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR (November 2000). "The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion". Endocrinology 141 (11): 4325–8. doi:10.1210/endo.141.11.7873. PMID 11089570.
- Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ (September 2003). "Hyperphagic effects of brainstem ghrelin administration". Diabetes 52 (9): 2260–5. PMID 12941764.
- Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG (April 2000). "Central nervous system control of food intake". Nature 404 (6778): 661–71. doi:10.1038/35007534 (inactive 5 March 2014). PMID 10766253.
- Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, Meijler MM, Janda KD (August 2006). "Vaccination against weight gain". Proc. Natl. Acad. Sci. U.S.A. 103 (35): 13226–31. Bibcode:2006PNAS..10313226Z. doi:10.1073/pnas.0605376103. PMC 1559781. PMID 16891413. Lay summary – The Scripps Research Institute.
- Vizcarra JA, Kirby JD, Kim SK, Galyean ML (August 2007). "Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs". Domest Anim Endocrinol. 33 (2): 176–89. doi:10.1016/j.domaniend.2006.05.005. PMID 16793235.
- Waseem T, Duxbury M, Ito H, Rocha F, Lautz D, Whang E, Ashley SW, Robinson MK (September 2004). "Ghrelin ameliorates TNF-a induced anti-proliferative and pro-apoptotic effects and promotes intestinal epithelial restitution". Journal of the American College of Surgeons 199 (3 Supplement): 16. doi:10.1016/j.jamcollsurg.2004.05.018.
- Waseem T, Duxbury M, Ito H, Ashley SW, Robinson MK (March 2008). "Exogenous ghrelin modulates release of pro- and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways". Surgery 143 (3): 334–42. doi:10.1016/j.surg.2007.09.039. PMC 2278045. PMID 18291254.
- Gonzalez-Rey E, Chorny A, Delgado M (May 2006). "Therapeutic action of ghrelin in a mouse model of colitis". Gastroenterology 130 (6): 1707–20. doi:10.1053/j.gastro.2006.01.041. PMID 16697735.
- Wu R, Dong W, Ji Y, Zhou M, Marini CP, Ravikumar TS, Wang P (2008). "Orexigenic Hormone Ghrelin Attenuates Local and Remote Organ Injury after Intestinal Ischemia-Reperfusion". PLoS ONE 3 (4): e2026. Bibcode:2008PLoSO...3.2026W. doi:10.1371/journal.pone.0002026. PMC 2295264. PMID 18431503.
- Işeri SO, Sener G, Yüksel M, Contuk G, Cetinel S, Gedik N, Yegen BC (December 2005). "Ghrelin against alendronate-induced gastric damage in rats". J. Endocrinol. 187 (3): 399–406. doi:10.1677/joe.1.06432. PMID 16423819.
- Waseem T (March 2009). "Commentary: Ghrelin's role in gastrointestinal tract cancer". Surg Oncol 19 (1): e1. doi:10.1016/j.suronc.2009.02.014. PMID 19324542.
- Waseem T, Javaid-Ur-Rehman, Ahmad F, Azam M, Qureshi MA (August 2008). "Role of ghrelin axis in colorectal cancer: a novel association". Peptides 29 (8): 1369–76. doi:10.1016/j.peptides.2008.03.020. PMID 18471933.
- Duxbury MS, Waseem T, Ito H, Robinson MK, Zinner MJ, Ashley SW, Whang EE (September 2003). "Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness". Biochem. Biophys. Res. Commun. 309 (2): 464–8. doi:10.1016/j.bbrc.2003.08.024. PMID 12951072.
- Stengel A, Taché Y (2012). "Ghrelin – a pleiotropic hormone secreted from endocrine x/a-like cells of the stomach". Front Neurosci 6: 24. doi:10.3389/fnins.2012.00024. PMC 3280431. PMID 22355282.
- Spencer SJ, Xu L, Clarke MA, Lemus M, Reichenbach A, Geenen B, Kozicz T, Andrews ZB (September 2012). "Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress". Biol. Psychiatry 72 (6): 457–65. doi:10.1016/j.biopsych.2012.03.010. PMID 22521145.
- Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM (July 2008). "The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress". Nat. Neurosci. 11 (7): 752–3. doi:10.1038/nn.2139. PMC 2765052. PMID 18552842.
- Taheri S, Lin L, Austin D, Young T, Mignot E (December 2004). "Short Sleep Duration Is Associated with Reduced Leptin, Elevated Ghrelin, and Increased Body Mass Index". PLoS Med. 1 (3): e62. doi:10.1371/journal.pmed.0010062. PMC 535701. PMID 15602591.
- Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA (October 2013). "A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear". Mol. Psychiatry. doi:10.1038/mp.2013.135. PMID 24126924. Lay summary – Massachusetts Institute of Technology News.
- Comninos AN, Jayasena CN, Dhillo WS (2014). "The relationship between gut and adipose hormones, and reproduction". Hum. Reprod. Update 20 (2): 153–74. doi:10.1093/humupd/dmt033. PMID 24173881.
- Santos M, Bastos P, Gonzaga S, Roriz JM, Baptista MJ, Nogueira-Silva C, Melo-Rocha G, Henriques-Coelho T, Roncon-Albuquerque R Jr, Leite-Moreira AF, De Krijger RR, Tibboel D, Rottier R, Correia-Pinto J (2006). "Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia". Pediatr Res 59 (4 Pt 1): 531–7. doi:10.1203/01.pdr.0000202748.66359.a9. PMID 16549524.
- Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (May 2002). "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery". N. Engl. J. Med. 346 (21): 1623–30. doi:10.1056/NEJMoa012908. PMID 12023994.
- Goldstone AP, Thomas EL, Brynes AE, Castroman G, Edwards R, Ghatei MA, Frost G, Holland AJ, Grossman AB, Korbonits M, Bloom SR, Bell JD (April 2004). "Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance". J. Clin. Endocrinol. Metab. 89 (4): 1718–26. doi:10.1210/jc.2003-031118. PMID 15070936.
- DelParigi A, Tschöp M, Heiman ML, Salbe AD, Vozarova B, Sell SM, Bunt JC, Tataranni PA (December 2002). "High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome". J. Clin. Endocrinol. Metab. 87 (12): 5461–4. doi:10.1210/jc.2002-020871. PMID 12466337.
- Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F, Bloom SR, Estour B (April 2007). = long&pmid = 17413094 "Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin". Am. J. Clin. Nutr. 85 (4): 967–71. PMID 17413094.
- Hotta M, Ohwada R, Akamizu T, Shibasaki T, Takano K, Kangawa K (2009). "Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: a pilot study". Endocr. J. 56 (9): 1119–28. doi:10.1507/endocrj.K09E-168. PMID 19755753.
- Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J (July 2004). "Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity". Proc. Natl. Acad. Sci. U.S.A. 101 (28): 10434–9. Bibcode:2004PNAS..10110434Y. doi:10.1073/pnas.0403465101. PMC 478601. PMID 15231997.
- Cappuccio FP, Taggart FM, Kandala NB, Currie A, Peile E, Stranges S, Miller MA (May 2008). "Meta-analysis of short sleep duration and obesity in children and adults". Sleep 31 (5): 619–26. PMC 2398753. PMID 18517032.
- Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, Smith RG, Cunningham GR, Marcelli M (May 2005). "Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia". J. Clin. Endocrinol. Metab. 90 (5): 2920–6. doi:10.1210/jc.2004-1788. PMID 15713718.
- Cummings DE, Shannon MH (July 2003). "Ghrelin and Gastric Bypass: Is There a Hormonal Contribution to Surgical Weight Loss?". J Clin Endocrinol Metab. 88 (7): 2999–3002. doi:10.1210/jc.2003-030705. PMID 12843132.
- Bohdjalian A, Langer FB, Shakeri-Leidenmühler S, Gfrerer L, Ludvik B, Zacherl J, Prager G. (May 2010). "Sleeve gastrectomy as sole and definitive bariatric procedure: 5-year results for weight loss and ghrelin.". Obes Surg. 20 (5): 535–40. doi:10.1007/s11695-009-0066-6. PMID 20094819.
- Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J, Elsworth JD, Savitt JM, DiMarchi R, Tschoep M, Roth RH, Gao XB, Horvath TL (November 2009). "Ghrelin promotes and protects nigrostriatal dopamine function via an UCP2-dependent mitochondrial mechanism". J. Neurosci. 29 (45): 14057–65. doi:10.1523/JNEUROSCI.3890-09.2009. PMC 2845822. PMID 19906954.
- Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA (October 2013). "A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear". Mol. Psychiatry. doi:10.1038/mp.2013.135. PMID 24126924.
- Dickson SL (January 2002). "Ghrelin: a newly discovered hormone". J. Neuroendocrinol. 14 (1): 83–4. PMID 11903816.
- Bown R (3 September 2006). "Ghrelin". Pathophysiology of the Endocrine System. Colorado State University. Retrieved 18 September 2008.
- Burstain T (1 January 2005). "Balancing Your Hunger Hormones". Web site reviewing role of ghrelin and leptin in obesity. Infinity Medical Systems, Inc. Retrieved 18 September 2008.
- Shea C (10 December 2006). = 1&scp = 1&sq = Empty-Stomach+Intelligence&st = nyt&oref = slogin "Empty-Stomach Intelligence". New York Times. Retrieved 18 September 2008.
- Raloff J (April 2005). "Still Hungry? Fattening revelations—and new mysteries—about the hunger hormone". Science News (ScienceNews.org) 167 (14): 216–220. doi:10.2307/4016366. JSTOR 4016366.
- Nixon R (14 July 2008). "Feeling hungry can make you happy". Mental health (MSNBC.com). Retrieved 18 September 2008.
- Tomasetto C (1 March 2001). "Ghrelin/MTLRP (motilin-related peptide)". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 18 September 2008.