Ghrelin (pr. GREL-in), the "hunger hormone", is a peptide produced by ghrelin cells in the gastrointestinal tract which functions as a neuropeptide in the central nervous system. Beyond regulating hunger, ghrelin also plays a significant role in regulating the distribution and rate of use of energy.
When the stomach is empty, ghrelin is secreted. When the stomach is stretched, secretion stops. It acts on hypothalamic brain cells both to increase hunger, and to increase gastric acid secretion and gastrointestinal motility to prepare the body for food intake.
The receptor for ghrelin is found on the same cells in the brain as the receptor for leptin, the satiety hormone that has opposite effects from ghrelin. Ghrelin also plays an important role in regulating reward perception in dopamine neurons that link the ventral tegmental area to the nucleus accumbens (a site that plays a role in processing sexual desire, reward, and reinforcement, and in developing addictions) through its colocalized receptors and interaction with dopamine and acetylcholine. Ghrelin is encoded by the GHRL gene and is produced from the presumed cleavage of the prepropeptide ghrelin/obestatin. Full-length preproghrelin is homologous to promotilin and both are members of the motilin family.
- 1 History and name
- 2 Gene, transcription products, and structure
- 3 Ghrelin cells
- 4 Function and mechanism of action
- 5 Blood levels
- 6 The ghrelin receptor
- 7 Sites of action
- 8 Immune system
- 9 Anorexia and obesity
- 10 Disease management
- 11 Future clinical uses
- 12 References
- 13 Further reading
History and name
Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHSR) was discovered in 1996 and was reported in 1999. The hormone 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)
Gene, transcription products, and structure
The GHRL gene produces mRNA which has four exons. Five products arise: the first is the 117-amino acid preproghrelin. (It is homologous to promotilin; both are members of the motilin family). It is cleaved to produce proghrelin which is cleaved to produce a 28-amino acid ghrelin (unacylated) and C-ghrelin(acylated). Obestatin is presumed to be cleaved from C-ghrelin.
Ghrelin only becomes active when caprylic (octanoic) acid is linked posttranslationally to serine at the 3-position by the enzyme ghrelin O-acyltransferase (GOAT). It is located on the cell membrane of ghrelin cells in the stomach and pancreas. The non-octanoylated form is desacyl ghrelin. It does not activate the GHSR receptor but does have other effects: cardiac, anti-ghrelin, appetite stimulation, and inhibition of hepatic glucose output Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor. In particular, decanoyl ghrelin has been found to constitute a significant portion of circulating ghrelin in mice, but as of 2011 its presence in humans has not been established.
The ghrelin cell is also known as an A-like cell (pancreas), X-cell (for unknown function), X/A-like cell (rats), Epsilon cell (pancreas), P/D sub 1 cell (humans) and Gr cell (abbreviation for ghrelin cell).
Ghrelin cells are found in oxyntic glands (20% of cells), pyloric glands, and small intestine. They are ovoid cells with granules. They have gastrin receptors. They produce nesfatin-1, another food intake limiting hormone in addition to ghrelin. Ghrelin cells are not terminally differentiated in the pancreas: they are progenitor cells that can give rise to A-cells, PP cells and Beta-cells there.
Function and mechanism of action
Ghrelin is a participant in the complex process of energy homeostasis which adjusts both energy input - by adjusting hunger signals - and energy output - by adjusting the proportion of energy going to ATP production, fat storage, and short-term heat loss (all energy input is ultimately dissipated as heat). The net result of these processes is reflected in body weight, and is under continuous monitoring and adjustment based on metabolic signals and needs and at any given moment in time may be in equilibrium or disequilibrium.. Gastric-brain communication is an essential part of energy homeostasis, and several communication pathways are probable, including the gastric intracellular mTOR/S6K1 pathway mediating the interaction among ghrelin, nesfatin and endocannabinoid gastric systems, and both afferent and efferent vagal signals.
Ghrelin and synthetic ghrelin mimetics (the growth hormone secretagogues) increase appetite and fat mass by triggering receptors in the arcuate nucleus that include the orexigenic neuropeptide Y (NPY) neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin reduces the mechanosensitivity of gastric vagal afferents, so they are less sensitive to gastric distension.
In addition to its function in energy homeostasis, ghrelin also activates the mesolimbic cholinergic–dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food and addictive drugs such as ethanol. Ghrelin receptors are located on neurons in this circuit. Hypothalamic ghrelin signalling is required for reward from alcohol and palatable/rewarding foods.
Ghrelin also improves endothelial function and inhibits proatherogenic changes in cell cultures. It activates the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.
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. 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. This suggests that ghrelin acts as a body weight regulator, continuously keeping one's body weight and energy stores in check.
Blood levels are in the pmol/l range. Both active and total ghrelin can be measured. Circulating ghrelin concentrations rise before eating and fall afterward, more strongly in response to protein and carbohydrate than to lipids.
The ghrelin receptor
The ghrelin receptor GHSR1a (a splice-variant of the growth hormone secretagogue receptor) is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of growth hormone release, increase in hunger, modulation of glucose and lipid metabolism, regulation of gastrointestinal motility and secretion, protection of neuronal and cardiovascular cells, and regulation of immune function. They are present in high density in the hypothalamus and pituitary, on the vagus nerve (on both afferent cell bodies and afferent nerve endings) and throughout the gastrointestinal tract.
Sites of action
Ghrelin promotes intestinal cell proliferation and inhibits apoptosis during inflammatory states and oxidative stress. It also suppresses 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. 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 mucosal injury to the stomach.
Ghrelin acts on its receptor in the pancreas to inhibit glucose-stimulated insulin secretion.
The entire ghrelin system (dAG, AG, GHSR and GOAT) has a gluco-regulatory action.
Learning and memory
The hippocampus plays a significant role in neurotrophy: the cognitive adaptation to changing environments and the process of learning and it is a potent stimulator of growth hormone. 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 on human memory performance 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 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 levels trend lower and obesity is less likely.
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.
Substantia nigra function
Fetus and neonate
- Ghrelin is produced early by the fetal lung and promotes lung growth.
- Cord blood levels of active and total ghrelin show a correlation between ghrelin levels and birth weight.
Ghrelin gene products have several actions on acute and chronic inflammation and autoimmunity, with promising therapeutic applications.
Anorexia and obesity
- 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 with anorexia nervosa have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls.
- 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 rhythm of obese individuals.
- Ghrelin levels reflect release in a circadian rhythm which can be interrupted by exposure to light at night.
- Short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes.
- Lack of sleep increases ghrelin, and decreases leptin, both effects producing increased hunger and obesity.
- Ghrelin levels are high in patients with cancer-induced cachexia.
Gastric bypass surgery
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.
Medical management of obesity
Future clinical uses
- Synthetic ghrelin administration for cachexia of any cause  and for hemodialysis patients is being investigated.
- Ghrelin suppresses seizures in animal models and is being investigated.
- Ghrelin is a gastric pro-kinetic and may be useful in the treatment of gastroparesis.
- Sakata I, Sakai T (2010). "Ghrelin cells in the gastrointestinal tract". Int J Pept 2010. doi:10.1155/2010/945056. PMC 2925405. PMID 20798855.
- 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.
- Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (2011). "The role of the central ghrelin system in reward from food and chemical drugs". Mol. Cell. Endocrinol. 340 (1): 80–87. doi:10.1016/j.mce.2011.02.017. PMID 21354264.
- Burger KS, Berner LA (2014). "A functional neuroimaging review of obesity, appetitive hormones and ingestive behavior". Physiol. Behav. doi:10.1016/j.physbeh.2014.04.025. PMID 24769220.
- 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.
- Perello M, Scott MM, Sakata I, Lee CE, Chuang JC, Osborne-Lawrence S, Rovinsky SA, Elmquist JK, Zigman JM (2012). "Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain". J. Comp. Neurol. 520 (2): 281–94. doi:10.1002/cne.22690. PMC 3282302. PMID 21674492.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10:Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 265–266. ISBN 9780071481274. "The best described site of action of ghrelin is the VMH and arcuate nucleus, but ghrelin receptors are also expressed in the brain’s reward pathways (eg, VTA dopamine neurons) and may stimulate feeding through this action as well. ... It is very interesting then, as mentioned above, that orexin, leptin, and ghrelin receptors are expressed in the VTA, and MC4 and MCH receptors are enriched in the nucleus accumbens. There is increasing evidence that some of the actions of these feeding peptides are mediated at the level of the VTA-NAc circuit: recent studies, for example, have shown that injection of leptin into the VTA suppresses feeding behavior, while RNAi (RNA interference; Chapter 4) mediated-knockdown of leptin receptors in the VTA increases food intake, sensitivity to highly palatable foods, and locomotor activity."
- Le Moal, Michel. "Mesocorticolimbic Dopaminergic Neurons". Neuropsychopharmacology: The Fifth Generation of Progress. Retrieved 21 May 2014.
- 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.
- 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.
- 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.
- Seim I, Amorim L, Walpole C, Carter S, Chopin LK, Herington AC (2010). "Ghrelin gene-related peptides: multifunctional endocrine / autocrine modulators in health and disease". Clin Exp Pharmacol Physiol. 37 (1): 125–31. doi:10.1111/j.1440-1681.2009.05241.x. PMID 19566830.
- 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.
- Stengel A, Taché Y (2011). "Interaction between Gastric and Upper Small Intestinal Hormones in the Regulation of Hunger and Satiety: Ghrelin and Cholecystokinin Take the Central Stage". Curr. Protein Pept. Sci. 12 (4): 293–304. doi:10.2174/138920311795906673. PMC 3670092. PMID 21428875.
- Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Williams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK (2005). "Mice lacking ghrelin receptors resist the development of diet-induced obesity". J. Clin. Invest. 115 (12): 3564–72. doi:10.1172/JCI26002. PMC 1297251. PMID 16322794.
- 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.
- Suckale J, Solimena M (2008). "Pancreas islets in metabolic signaling--focus on the beta-cell". Front. Biosci. 13: 7156–71. doi:10.2741/3218. PMID 18508724.
- Simonsson M, Eriksson S, Håkanson R, Lind T, Lönroth H, Lundell L, O'Connor DT, Sundler F (1988). "Endocrine cells in the human oxyntic mucosa. A histochemical study". Scand. J. Gastroenterol. 23 (9): 1089–99. doi:10.3109/00365528809090174. PMID 2470131.
- Grube D, Forssmann WG (1979). "Morphology and function of the entero-endocrine cells". Horm. Metab. Res. 11 (11): 589–606. doi:10.1055/s-0028-1092785. PMID 94030.
- Fukumoto K, Nakahara K, Katayama T, Miyazatao M, Kangawa K, Murakami N (2008). "Synergistic action of gastrin and ghrelin on gastric acid secretion in rats". Biochem. Biophys. Res. Commun. 374 (1): 60–3. doi:10.1016/j.bbrc.2008.06.114. PMID 18611393.
- Inhoff T, Stengel A, Peter L, Goebel M, Taché Y, Bannert N, Wiedenmann B, Klapp BF, Mönnikes H, Kobelt P (2010). "Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats". Peptides 31 (2): 257–62. doi:10.1016/j.peptides.2009.11.024. PMC 4043136. PMID 19961888.
- Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L (2012). "Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population". PLoS ONE 7 (12): e52026. doi:10.1371/journal.pone.0052026. PMC 3520898. PMID 23251675.
- Folgueira C, Seoane LM, Casanueva FF (2014). "The brain-stomach connection". Front Horm Res 42: 83–92. doi:10.1159/000358316. PMID 24732927.
- 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.
- 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.
- 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.
- 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.
- 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. doi:10.2337/diabetes.52.9.2260. PMID 12941764.
- Yokota I, Kitamura S, Hosoda H, Kotani Y, Kangawa K (2005). "Concentration of the n-octanoylated active form of ghrelin in fetal and neonatal circulation". Endocr. J. 52 (2): 271–6. doi:10.1507/endocrj.52.271. PMID 15863960.
- Yin Y, Li Y, Zhang W (2014). "The growth hormone secretagogue receptor: its intracellular signaling and regulation". Int J Mol Sci 15 (3): 4837–55. doi:10.3390/ijms15034837. PMC 3975427. PMID 24651458.
- 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.
- Heppner KM, Tong J (2014). "Regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions". Eur. J. Endocrinol. 171 (1): R21–32. doi:10.1530/EJE-14-0183. PMID 24714083.
- 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.
- 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.
- 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.
- 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.
- Prodam F, Filigheddu N (2014). "Ghrelin Gene Products in Acute and Chronic Inflammation". Arch. Immunol. Ther. Exp. (Warsz.). doi:10.1007/s00005-014-0287-9. PMID 24728531.
- 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.
- Misra M, Klibanski A (2014). "Endocrine consequences of anorexia nervosa". Lancet Diabetes Endocrinol 2 (7): 581–592. doi:10.1016/S2213-8587(13)70180-3. PMID 24731664.
- Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F, Bloom SR, Estour B (April 2007). "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.
- Fonken LK, Nelson RJ (2014). "The Effects of Light at Night on Circadian Clocks and Metabolism". Endocr. Rev. 35 (4): er20131051. doi:10.1210/er.2013-1051. PMID 24673196.
- 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.
- 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.
- Berardi E, Annibali D, Cassano M, Crippa S, Sampaolesi M (2014). "Molecular and cell-based therapies for muscle degenerations: a road under construction". Front Physiol 5: 119. doi:10.3389/fphys.2014.00119. PMC 3986550. PMID 24782779.
- Ruperto M, Sánchez-Muniz FJ, Barril G (2014). "A clinical approach to the nutritional care process in protein-energy wasting hemodialysis patients". Nutr Hosp 29 (4): 735–50. doi:10.3305/nh.2014.29.4.7222. PMID 24679014.
- Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM (2014). "Neuropeptides as Targets for the Development of Anticonvulsant Drugs". Mol. Neurobiol. doi:10.1007/s12035-014-8669-x. PMID 24705860.
- Hasler WL (2014). "Emerging drugs for the treatment of gastroparesis". Expert Opin Emerg Drugs 19 (2): 261–79. doi:10.1517/14728214.2014.899353. PMID 24669936.
- 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.