Ghrelin (pronounced "GREL-in"), the "hunger hormone", also known as lenomorelin (INN), is a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract which functions as a neuropeptide in the central nervous system. Besides regulating appetite, 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, the ghrelin/growth hormone secretagogue receptor (GHSR), 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 presumably produced from the 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 Ghrelin receptor
- 7 Locations of action
- 8 Immune system
- 9 Anorexia and obesity
- 10 Disease management
- 11 Aging
- 12 Future clinical uses
- 13 References
- 14 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 regulating 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, glycogen 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. At any given moment in time, it 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 (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 GHSR1a (a splice-variant of the growth hormone secretagogue receptor, with the GHSR1b splice being inactive) 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.
Locations 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.
- 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 nearly 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
Ghrelin is not FDA approved for any indication.
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". International Journal of Peptides 2010: 1. doi:10.1155/2010/945056. PMC 2925405. PMID 20798855.
- Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM et al. (Mar 2004). "Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ". FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 18 (3): 439–56. doi:10.1096/fj.03-0641rev. PMID 15003990.
- Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (Jun 2011). "The role of the central ghrelin system in reward from food and chemical drugs". Molecular and Cellular Endocrinology 340 (1): 80–87. doi:10.1016/j.mce.2011.02.017. PMID 21354264.
- Burger KS, Berner LA (Sep 2014). "A functional neuroimaging review of obesity, appetitive hormones and ingestive behavior". Physiology & Behavior 136: 121–7. doi:10.1016/j.physbeh.2014.04.025. PMID 24769220.
- Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG (Apr 2000). "Central nervous system control of food intake". Nature 404 (6778): 661–71. doi:10.1038/35007534 (inactive 2015-02-01). PMID 10766253.
- Perello M, Scott MM, Sakata I, Lee CE, Chuang JC, Osborne-Lawrence S et al. (Feb 2012). "Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain". The Journal of Comparative Neurology 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 M (2002). "Mesocorticolimbic Dopaminergic Neurons". In Davis KL, Charney D, Coyle JT, Nemeroff C. Neuropsychopharmacology : the fifth generation of progress : an official publication of the American College of Neuropsychopharmacology (5th ed.). Philadelphia, Pa.: Lippincott Williams & Wilkins. ISBN 978-0781728379.
- Veldhuis, Johannes D.; Bowers, Cyril Y. (2010). "Integrating GHS into the Ghrelin System". International Journal of Peptides 2010: 1–40. doi:10.1155/2010/879503. ISSN 1687-9767.
- Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI et al. (Aug 1996). "A receptor in pituitary and hypothalamus that functions in growth hormone release". Science (New York, N.Y.) 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 (Dec 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 et al. (Mar 2004). "Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ". FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 18 (3): 439–56. doi:10.1096/fj.03-0641rev. PMID 15003990.
- Seim I, Amorim L, Walpole C, Carter S, Chopin LK, Herington AC (Jan 2010). "Ghrelin gene-related peptides: multifunctional endocrine / autocrine modulators in health and disease". Clinical and Experimental Pharmacology & Physiology 37 (1): 125–31. doi:10.1111/j.1440-1681.2009.05241.x. PMID 19566830.
- Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH (Jan 2010). "Ghrelin in the regulation of body weight and metabolism". Frontiers in Neuroendocrinology 31 (1): 44–60. doi:10.1016/j.yfrne.2009.10.008. PMID 19896496.
- Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghé C et al. (Aug 2003). "Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin". European Journal of Pharmacology 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 et al. (Jun 2004). "Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans". The Journal of Clinical Endocrinology and Metabolism 89 (6): 3062–5. doi:10.1210/jc.2003-031964. PMID 15181099.
- Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T et al. (May 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 et al. (Feb 2005). "Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes". The Journal of Clinical Endocrinology and Metabolism 90 (2): 1055–6. doi:10.1210/jc.2004-1069. PMID 15536157.
- Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB (Apr 2004). "Ghrelin--a hormone with multiple functions". Frontiers in Neuroendocrinology 25 (1): 27–68. doi:10.1016/j.yfrne.2004.03.002. PMID 15183037.
- Stengel A, Taché Y (Jun 2011). "Interaction between gastric and upper small intestinal hormones in the regulation of hunger and satiety: ghrelin and cholecystokinin take the central stage". Current Protein & Peptide Science 12 (4): 293–304. doi:10.2174/138920311795906673. PMC 3670092. PMID 21428875.
- Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE et al. (Dec 2005). "Mice lacking ghrelin receptors resist the development of diet-induced obesity". The Journal of Clinical Investigation 115 (12): 3564–72. doi:10.1172/JCI26002. PMC 1297251. PMID 16322794.
- Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T et al. (Oct 2001). "Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans". The Journal of Clinical Endocrinology and Metabolism 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". Frontiers in Bioscience : A Journal and Virtual Library 13 (13): 7156–71. doi:10.2741/3218. PMID 18508724.
- Simonsson M, Eriksson S, Håkanson R, Lind T, Lönroth H, Lundell L et al. (Nov 1988). "Endocrine cells in the human oxyntic mucosa. A histochemical study". Scandinavian Journal of Gastroenterology 23 (9): 1089–99. doi:10.3109/00365528809090174. PMID 2470131.
- Grube D, Forssmann WG (Nov 1979). "Morphology and function of the entero-endocrine cells". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme 11 (11): 589–606. doi:10.1055/s-0028-1092785. PMID 94030.
- Fukumoto K, Nakahara K, Katayama T, Miyazatao M, Kangawa K, Murakami N (Sep 2008). "Synergistic action of gastrin and ghrelin on gastric acid secretion in rats". Biochemical and Biophysical Research Communications 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 et al. (Feb 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. Bibcode:2012PLoSO...752026A. doi:10.1371/journal.pone.0052026. PMC 3520898. PMID 23251675.
- Folgueira C, Seoane LM, Casanueva FF (2014). "The brain-stomach connection". Frontiers of Hormone Research. Frontiers of Hormone Research 42: 83–92. doi:10.1159/000358316. ISBN 978-3-318-02638-2. PMID 24732927.
- Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL (Jan 2001). "Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues". Biochemical and Biophysical Research Communications 280 (1): 132–138. doi:10.1006/bbrc.2000.4065. PMID 11162489.
- Tschöp M, Smiley DL, Heiman ML (Oct 2000). "Ghrelin induces adiposity in rodents". Nature 407 (6806): 908–913. doi:10.1038/35038090. PMID 11057670.
- Hewson AK, Dickson SL (Nov 2000). "Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats". Journal of Neuroendocrinology 12 (11): 1047–1049. doi:10.1046/j.1365-2826.2000.00584.x. PMID 11069119.
- Dickson SL, Leng G, Robinson IC (Mar 1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience 53 (2): 303–306. doi:10.1016/0306-4522(93)90197-N. PMID 8492908.
- Dickson SL, Luckman SM (Feb 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 (Dec 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 AJ, Slattery JA, Milte C, Laker R, O'Donnell T, Dorian C et al. (May 2007). "Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents". American Journal of Physiology. Gastrointestinal and Liver Physiology 292 (5): 1376–1384. doi:10.1152/ajpgi.00536.2006. PMID 17290011.
- Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA (Mar 2006). "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 (Mar 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 et al. (Jul 2009). "Requirement of central ghrelin signaling for alcohol reward". Proceedings of the National Academy of Sciences of the United States of America 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 et al. (Jul 2010). "Ghrelin increases intake of rewarding food in rodents". Addiction Biology 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 (Jan 2012). "Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression". Addiction Biology 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 (Aug 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 (Aug 2004). "Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues". American Journal of Physiology. Endocrinology and Metabolism 287 (2): E297–304. doi:10.1152/ajpendo.00582.2003. PMID 15039149.
- Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S et al. (Nov 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 (Sep 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 (Apr 2005). "Concentration of the n-octanoylated active form of ghrelin in fetal and neonatal circulation". Endocrine Journal 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". International Journal of Molecular Sciences 15 (3): 4837–55. doi:10.3390/ijms15034837. PMC 3975427. PMID 24651458.
- Waseem T, Duxbury M, Ito H, Rocha F, Lautz D, Whang E et al. (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 (Mar 2008). "Exogenous ghrelin modulates release of pro-inflammatory 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 et al. (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 et al. (Dec 2005). "Ghrelin against alendronate-induced gastric damage in rats". The Journal of Endocrinology 187 (3): 399–406. doi:10.1677/joe.1.06432. PMID 16423819.
- Waseem T (Mar 2010). "Commentary: Ghrelin's role in gastrointestinal tract cancer". Surgical Oncology 19 (1): e1. doi:10.1016/j.suronc.2009.02.014. PMID 19324542.
- Waseem T, Ahmad F, Azam M, Qureshi MA (Aug 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 et al. (Sep 2003). "Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness". Biochemical and Biophysical Research Communications 309 (2): 464–8. doi:10.1016/j.bbrc.2003.08.024. PMID 12951072.
- Heppner KM, Tong J (Jul 2014). "Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions". European Journal of Endocrinology / European Federation of Endocrine Societies 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 et al. (Mar 2006). "Ghrelin controls hippocampal spine synapse density and memory performance". Nature Neuroscience 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 et al. (Oct 2009). "Cognitive enhancing effects of ghrelin receptor agonists". Psychopharmacology 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". Frontiers in Neuroscience 6: 24. doi:10.3389/fnins.2012.00024. PMC 3280431. PMID 22355282.
- Spencer SJ, Xu L, Clarke MA, Lemus M, Reichenbach A, Geenen B et al. (Sep 2012). "Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress". Biological 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 et al. (Jul 2008). "The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress". Nature Neuroscience 11 (7): 752–3. doi:10.1038/nn.2139. PMC 2765052. PMID 18552842.
- Taheri S, Lin L, Austin D, Young T, Mignot E (Dec 2004). "Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index". PLoS Medicine 1 (3): e62. doi:10.1371/journal.pmed.0010062. PMC 535701. PMID 15602591.
- Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA (Dec 2014). "A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear". Molecular Psychiatry 19 (12): 1284–94. doi:10.1038/mp.2013.135. PMC 3988273. PMID 24126924. Lay summary – Massachusetts Institute of Technology News.
- Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J et al. (Nov 2009). "Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 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". Human Reproduction 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 et al. (Apr 2006). "Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia". Pediatric Research 59 (4 Pt 1): 531–7. doi:10.1203/01.pdr.0000202748.66359.a9. PMID 16549524.
- Prodam F, Filigheddu N (Oct 2014). "Ghrelin gene products in acute and chronic inflammation". Archivum Immunologiae Et Therapiae Experimentalis 62 (5): 369–84. doi:10.1007/s00005-014-0287-9. PMID 24728531.
- Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP et al. (May 2002). "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery". The New England Journal of Medicine 346 (21): 1623–30. doi:10.1056/NEJMoa012908. PMID 12023994.
- Goldstone AP, Thomas EL, Brynes AE, Castroman G, Edwards R, Ghatei MA et al. (Apr 2004). "Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance". The Journal of Clinical Endocrinology and Metabolism 89 (4): 1718–26. doi:10.1210/jc.2003-031118. PMID 15070936.
- DelParigi A, Tschöp M, Heiman ML, Salbe AD, Vozarova B, Sell SM et al. (Dec 2002). "High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome". The Journal of Clinical Endocrinology and Metabolism 87 (12): 5461–4. doi:10.1210/jc.2002-020871. PMID 12466337.
- Misra M, Klibanski A (Jul 2014). "Endocrine consequences of anorexia nervosa". The Lancet. Diabetes & Endocrinology 2 (7): 581–592. doi:10.1016/S2213-8587(13)70180-3. PMC 4133106. PMID 24731664.
- Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F et al. (Apr 2007). "Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin". The American Journal of Clinical Nutrition 85 (4): 967–71. PMID 17413094.
- Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J (Jul 2004). "Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity". Proceedings of the National Academy of Sciences of the United States of America 101 (28): 10434–9. Bibcode:2004PNAS..10110434Y. doi:10.1073/pnas.0403465101. PMC 478601. PMID 15231997.
- Fonken LK, Nelson RJ (Apr 2014). "The effects of light at night on circadian clocks and metabolism". Endocrine Reviews 35 (4): 648–70. doi:10.1210/er.2013-1051. PMID 24673196.
- Cappuccio FP, Taggart FM, Kandala NB, Currie A, Peile E, Stranges S et al. (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 et al. (May 2005). "Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia". The Journal of Clinical Endocrinology and Metabolism 90 (5): 2920–6. doi:10.1210/jc.2004-1788. PMID 15713718.
- Cummings DE, Shannon MH (Jul 2003). "Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss?". The Journal of Clinical Endocrinology and Metabolism 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 et al. (May 2010). "Sleeve gastrectomy as sole and definitive bariatric procedure: 5-year results for weight loss and ghrelin". Obesity Surgery 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 et al. (Aug 2006). "Vaccination against weight gain". Proceedings of the National Academy of Sciences of the United States of America 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 (Aug 2007). "Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs". Domestic Animal Endocrinology 33 (2): 176–89. doi:10.1016/j.domaniend.2006.05.005. PMID 16793235.
- Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS (Aug 2001). "A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans". Diabetes 50 (8): 1714–9. PMID 11473029.
- Karasu SR, Karasu TB (2010). The gravity of weight: a clinical guide to weight loss and maintenance (1st ed.). Washington, DC: American Psychiatric Publishing. p. 162. ISBN 978-1585623600.
- Berardi E, Annibali D, Cassano M, Crippa S, Sampaolesi M (2014). "Molecular and cell-based therapies for muscle degenerations: a road under construction". Frontiers in Physiology 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". Nutrición Hospitalaria 29 (4): 735–50. doi:10.3305/nh.2014.29.4.7222 (inactive 2015-02-01). PMID 24679014.
- Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM (Oct 2014). "Neuropeptides as targets for the development of anticonvulsant drugs". Molecular Neurobiology 50 (2): 626–46. doi:10.1007/s12035-014-8669-x. PMC 4182642. PMID 24705860.
- Hasler WL (Jun 2014). "Emerging drugs for the treatment of gastroparesis". Expert Opinion on Emerging Drugs 19 (2): 261–79. doi:10.1517/14728214.2014.899353. PMID 24669936.
- Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA (Dec 2014). "A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear". Molecular Psychiatry 19 (12): 1284–94. doi:10.1038/mp.2013.135. PMC 3988273. PMID 24126924.
- Dickson SL (Jan 2002). "Ghrelin: a newly discovered hormone". Journal of Neuroendocrinology 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.