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{{GNF_Protein_box
{{Use dmy dates|date=March 2016}}
| image = 
{{Infobox gene}}
| image_source = 
| PDB =
| Name = Ghrelin/obestatin preprohormone
| HGNCid = 18129
| Symbol = GHRL
| AltSymbols =; MTLRP; ghrelin; obestatin
| OMIM = 605353
| ECnumber = 
| Homologene = 9487
| MGIid = 1930008
| Function = {{GNF_GO|id=GO:0016608 |text = growth hormone-releasing hormone activity}} {{GNF_GO|id=GO:0031768 |text = ghrelin receptor binding}}  
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0008343 |text = adult feeding behavior}} {{GNF_GO|id=GO:0009755 |text = hormone-mediated signaling}} {{GNF_GO|id=GO:0030252 |text = growth hormone secretion}} {{GNF_GO|id=GO:0032100 |text = positive regulation of appetite}} {{GNF_GO|id=GO:0040018 |text = positive regulation of body size}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 51738
    | Hs_Ensembl = ENSG00000157017
    | Hs_RefseqProtein = NP_057446
    | Hs_RefseqmRNA = NM_016362
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 3
    | Hs_GenLoc_start = 10302434
    | Hs_GenLoc_end = 10307535
    | Hs_Uniprot = Q9UBU3
    | Mm_EntrezGene = 58991
    | Mm_Ensembl = ENSMUSG00000064177
    | Mm_RefseqmRNA = NM_021488
    | Mm_RefseqProtein = NP_067463
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 113681896
    | Mm_GenLoc_end = 113685657
    | Mm_Uniprot = Q9EQX0
  }}
}}
{{SI}}
__NOTOC__
{{GS}}


'''Ghrelin''' (pronounced {{IPAc-en|ˈ|ɡ|r|ɛ|l|ɪ|n|}}), the "hunger hormone", also known as '''lenomorelin''' ([[International Nonproprietary Name|INN]]), is a [[peptide hormone]] produced by ghrelinergic cells in the [[gastrointestinal tract]]<ref name="Sakata_2010">{{cite journal | vauthors = Sakata I, Sakai T | title = Ghrelin cells in the gastrointestinal tract | journal = International Journal of Peptides | volume = 2010 | issue =  | pages = 1–7 | year = 2010 | pmid = 20798855 | pmc = 2925405 | doi = 10.1155/2010/945056 }}</ref><ref>{{cite journal | vauthors = Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M | title = Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ | journal = The FASEB Journal | volume = 18 | issue = 3 | pages = 439–56  | date = March 2004 | pmid = 15003990 | doi = 10.1096/fj.03-0641rev | citeseerx = 10.1.1.325.45 }}</ref> that functions as a [[neuropeptide]] in the [[central nervous system]].<ref name="Cholinergic-dopaminergic reward link" /> Besides regulating [[appetite]], ghrelin also plays a significant role in regulating the [[Energy homeostasis|distribution and rate of use of energy]].<ref name="pmid24769220">{{cite journal | vauthors = Burger KS, Berner LA | title = A functional neuroimaging review of obesity, appetitive hormones and ingestive behavior | journal = Physiology & Behavior | volume = 136 | issue =  | pages = 121–27  | date = September 2014 | pmid = 24769220 | pmc = 4519076 | doi = 10.1016/j.physbeh.2014.04.025 }}</ref>


When the stomach is empty, ghrelin is secreted. When the stomach is stretched, secretion stops.{{ref|reference_name_A|a}} 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.<ref name = "Schwartz_2000">{{cite journal | vauthors = Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG|authorlink4=Randy Seeley|authorlink1=Michael Warren Schwartz | title = Central nervous system control of food intake | journal = Nature | volume = 404 | issue = 6778 | pages = 661–71 | date = April 2000 | pmid = 10766253 | doi = 10.1038/35007534 }}</ref>


'''Ghrelin''' is a [[hormone]] produced mainly by [[P/D1 cell]]s lining the [[fundus (stomach)|fundus]] of the human [[stomach]] that stimulate [[appetite]].<ref>{{cite journal |author=Inui A, Asakawa A, Bowers CY, ''et al'' |title=Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ |journal=FASEB J. |volume=18 |issue=3 |pages=439-56 |year=2004 |pmid=15003990 |doi=10.1096/fj.03-0641rev |url=http://www.fasebj.org/cgi/content/full/18/3/439}}</ref> 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. Ghrelin is also produced in the hypothalamic arcuate nucleus where it stimulates the secretion of [[growth hormone]] from the [[anterior pituitary gland]].<ref>{{cite journal |author= Mondal, M.S., Date, Y., Yamaguchi, H., Toshinai, K., Tsuruta, T., Kangawa, K., Nakazato, M.|title= Identification of ghrelin and its receptor in neurons of the rat arcuate nucleus |journal= Regul. Pept |volume=126 |pages=55-59|year=2005}}</ref> In some [[bariatrics|bariatric]] procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.
The receptor for ghrelin, the [[growth hormone secretagogue receptor|ghrelin/growth hormone secretagogue receptor]] (GHS-R), is found on the same cells in the brain as the receptor for [[leptin]], the satiety hormone that has opposite effects from ghrelin.<ref name="pmid21674492">{{cite journal | vauthors = Perello M, Scott MM, Sakata I, Lee CE, Chuang JC, Osborne-Lawrence S, Rovinsky SA, Elmquist JK, Zigman JM | title = Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain | journal = The Journal of Comparative Neurology | volume = 520 | issue = 2 | pages = 281–94  | date = February 2012 | pmid = 21674492 | pmc = 3282302 | doi = 10.1002/cne.22690 }}</ref> Ghrelin also plays an important role in regulating ''reward perception'' in [[mesolimbic pathway|dopamine neurons]] that link the [[ventral tegmental area]] to the [[nucleus accumbens]]<ref name="pmid16137788">{{cite journal |vauthors=Naleid AM, Grace MK, Cummings DE, Levine AS |title=Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens |journal=Peptides |volume=26 |issue=11 |pages=2274–79 |year=2005 |pmid=16137788 |doi=10.1016/j.peptides.2005.04.025 }}</ref><ref name="NHM-Ghrelin">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 265–66 | edition = 2nd | chapter = Chapter 10:Neural and Neuroendocrine Control of the Internal Milieu | quote=}}</ref> (a site that plays a role in processing sexual desire, [[reward system|reward]], and [[reinforcement]], and in developing addictions) through its [[wikt:colocalize|colocalized]] receptors and interaction with [[dopamine]] and [[acetylcholine]].<ref name="Cholinergic-dopaminergic reward link">{{cite journal | vauthors = Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E | title = The role of the central ghrelin system in reward from food and chemical drugs | journal = Molecular and Cellular Endocrinology | volume = 340 | issue = 1 | pages = 80–87  | date = June 2011 | pmid = 21354264 | doi = 10.1016/j.mce.2011.02.017 | quote = Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link".| hdl = 2077/26318 }}</ref><ref name="Mesocorticolimbic projection">{{cite book |veditors=Davis KL, Charney D, Coyle JT, Nemeroff C | title = Neuropsychopharmacology : the fifth generation of progress : an official publication of the American College of Neuropsychopharmacology | date = 2002 | publisher = Lippincott Williams & Wilkins | location = Philadelphia, Pa. | isbn = 978-0781728379 | edition = 5th | author = Le Moal M | chapter = Mesocorticolimbic Dopaminergic Neurons | chapterurl = http://www.acnp.org/g4/gn401000025/ch025.html}}</ref> 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.


Receptors for ghrelin are expressed by neurons in the [[arcuate nucleus]] and the [[ventromedial hypothalamus]]. The ghrelin receptor is a [[G protein-coupled receptor]], formerly known as the GHS receptor ([[growth hormone secretagogue receptor]]).  Ghrelin is also made by a small population of neurons in the arcuate nucleus.  Ghrelin plays a significant role in [[neurotrophy]], particularly in the [[hippocampus]], and is essential for cognitive adaptation to changing environments and the process of [[learning]].<ref>{{cite web |url=http://www.the-scientist.com/news/display/23132/ |title= Hunger hormone tied to learning |format= |work=}} at The Scientist</ref> Recently, ghrelin has been shown to activate the [[endothelial]] [[isoform]] of [[nitric oxide synthase]] in a pathway that depends on various [[kinase]]s including [[Akt]].
Unlike the case of many other [[endogenous]] [[peptide]]s, ghrelin is able to cross the [[blood-brain-barrier]], giving [[exogenous]]ly-administered ghrelin unique [[clinical use|clinical potential]].<ref name="VeldhuisBowers2010">{{cite journal|last1=Veldhuis|first1=Johannes D.|last2=Bowers|first2=Cyril Y.|title=Integrating GHS into the Ghrelin System|journal=International Journal of Peptides|volume=2010|year=2010|pages=1–40|issn=1687-9767|doi=10.1155/2010/879503|pmid=20798846|pmc=2925380}}</ref>


==Forms==
==History and name==
Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHS-R) was discovered in 1996<ref name = "Howard_1996">{{cite journal | vauthors = 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 | title = A receptor in pituitary and hypothalamus that functions in growth hormone release | journal = Science | volume = 273 | issue = 5277 | pages = 974–77 | date = August 1996 | pmid = 8688086 | doi = 10.1126/science.273.5277.974 | bibcode = 1996Sci...273..974H }}</ref> and was reported in 1999.<ref name="Kojima M, Hosoda H, Date Y, Nakazato M, Chris DeCaney, Matsuo H, Kangawa K 1999 656–60" /> The hormone name is based on its role as a '''''g'''rowth '''h'''ormone-'''re'''leasing peptide'', with reference to the [[Proto-Indo-European language|Proto-Indo-European]] root ''[[wiktionary:Reconstruction:Proto-Indo-European/gʰreh₁-|gʰre-]]'', meaning "to grow".<ref name = "pmid15003990">{{cite journal | vauthors = Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M | title = Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ | journal = The FASEB Journal | volume = 18 | issue = 3 | pages = 439–56 | date = March 2004 | pmid = 15003990 | doi = 10.1096/fj.03-0641rev | citeseerx = 10.1.1.325.45 }}</ref>
 
==Gene, transcription products, and structure==
[[File:Preproghrelin 1P7X.png|thumb|Preproghrelin (green and blue) and ghrelin (green).]]
The ''GHRL'' gene produces [[mRNA]] which has four [[exon]]s. 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.<ref name = "pmid19566830">{{cite journal | vauthors = Seim I, Amorim L, Walpole C, Carter S, Chopin LK, Herington AC | title = Ghrelin gene-related peptides: multifunctional endocrine / autocrine modulators in health and disease | journal = Clinical and Experimental Pharmacology & Physiology | volume = 37 | issue = 1 | pages = 125–31  | date = January 2010 | pmid = 19566830 | doi = 10.1111/j.1440-1681.2009.05241.x }}</ref>
 
Ghrelin only becomes active when [[caprylic acid|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]].<ref name = "pmid19896496"/> The non-octanoylated form is desacyl ghrelin. It does not activate the GHS-R receptor but does have other effects: cardiac,<ref>{{cite journal | vauthors = Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghé C, Deghenghi R, Ghigo E, Muccioli G | title = Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin | journal = European Journal of Pharmacology | volume = 476 | issue = 1–2 | pages = 87–95  | date = August 2003 | pmid = 12969753 | doi = 10.1016/S0014-2999(03)02083-1 | hdl = 2318/125949 }}</ref> anti-ghrelin,<ref>{{cite journal | vauthors = Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, Van Der Lely AJ, Ghigo E | title = Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 6 | pages = 3062–65  | date = June 2004 | pmid = 15181099 | doi = 10.1210/jc.2003-031964 }}</ref> appetite stimulation,<ref>{{cite journal | vauthors = 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 | title = Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor | journal = Endocrinology | volume = 147 | issue = 5 | pages = 2306–14  | date = May 2006 | pmid = 16484324 | doi = 10.1210/en.2005-1357 }}</ref> and inhibition of hepatic glucose output<ref>{{cite journal | vauthors = Gauna C, Delhanty PJ, Hofland LJ, Janssen JA, Broglio F, Ross RJ, Ghigo E, van der Lely AJ | title = Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 90 | issue = 2 | pages = 1055–56  | date = February 2005 | pmid = 15536157 | doi = 10.1210/jc.2004-1069 }}</ref> Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor.<ref>{{cite journal | vauthors = Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB | title = Ghrelin – a hormone with multiple functions | journal = Frontiers in Neuroendocrinology | volume = 25 | issue = 1 | pages = 27–68  | date = April 2004 | pmid = 15183037 | doi = 10.1016/j.yfrne.2004.03.002 }}</ref>  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.<ref name = "Stengel_Tache_2011" >{{cite journal | vauthors = Stengel A, Taché Y | title = Interaction between gastric and upper small intestinal hormones in the regulation of hunger and satiety: ghrelin and cholecystokinin take the central stage | journal = Current Protein & Peptide Science | volume = 12 | issue = 4 | pages = 293–304  | date = June 2011 | pmid = 21428875 | pmc = 3670092 | doi = 10.2174/138920311795906673 }}</ref>
 
==Ghrelin cells==
 
===Alternative names===
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).<ref name="pmid16322794">{{cite journal | vauthors = 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 | title = Mice lacking ghrelin receptors resist the development of diet-induced obesity | journal = The Journal of Clinical Investigation | volume = 115 | issue = 12 | pages = 3564–72  | date = December 2005 | pmid = 16322794 | pmc = 1297251 | doi = 10.1172/JCI26002 }}</ref>
 
===Location===
Ghrelin cells are found mainly in the stomach<ref name = "pmid11600536">{{cite journal | vauthors = 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 | title = Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 10 | pages = 4753–58 | date = October 2001 | pmid = 11600536 | doi = 10.1210/jcem.86.10.7885 }}</ref> and duodenum, but also in the jejunum, lungs, pancreatic islets,<ref name="pmid18508724">{{cite journal | vauthors = Suckale J, Solimena M | title = Pancreas islets in metabolic signaling—focus on the beta-cell | journal = Frontiers in Bioscience | volume = 13 | issue = 13 | pages = 7156–71 | year = 2008 | pmid = 18508724 | doi = 10.2741/3218 }}</ref> gonads, adrenal cortex, placenta, and kidney. It has recently been shown that ghrelin is produced locally in the brain<ref>{{cite journal |vauthors=Ferrini F, Salio C, Lossi L, Merighi A | year = 2009 | title = Ghrelin in Central Neurons | url = | journal = Current Neuropharmacology | volume = 7 | issue = 1| pages = 37–49 | doi = 10.2174/157015909787602779 | pmid = 19721816 | pmc = 2724662 }}</ref>
 
===Features===
Ghrelin cells are found in [[parietal cells|oxyntic glands]] (20% of cells),<ref name="pmid2470131">{{cite journal | vauthors = Simonsson M, Eriksson S, Håkanson R, Lind T, Lönroth H, Lundell L, O'Connor DT, Sundler F | title = Endocrine cells in the human oxyntic mucosa. A histochemical study | journal = Scandinavian Journal of Gastroenterology | volume = 23 | issue = 9 | pages = 1089–99  | date = November 1988 | pmid = 2470131 | doi = 10.3109/00365528809090174 }}</ref> pyloric glands, and small intestine.
They are ovoid cells with granules.<ref name="pmid94030">{{cite journal | vauthors = Grube D, Forssmann WG | title = Morphology and function of the entero-endocrine cells | journal = Hormone and Metabolic Research | volume = 11 | issue = 11 | pages = 589–606  | date = November 1979 | pmid = 94030 | doi = 10.1055/s-0028-1092785 }}</ref> They have gastrin receptors.<ref name="pmid18611393">{{cite journal | vauthors = Fukumoto K, Nakahara K, Katayama T, Miyazatao M, Kangawa K, Murakami N | title = Synergistic action of gastrin and ghrelin on gastric acid secretion in rats | journal = Biochemical and Biophysical Research Communications | volume = 374 | issue = 1 | pages = 60–63  | date = September 2008 | pmid = 18611393 | doi = 10.1016/j.bbrc.2008.06.114 }}</ref> Some produce nesfatin-1.<ref name="pmid19961888">{{cite journal | vauthors = Inhoff T, Stengel A, Peter L, Goebel M, Taché Y, Bannert N, Wiedenmann B, Klapp BF, Mönnikes H, Kobelt P | title = Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats | journal = Peptides | volume = 31 | issue = 2 | pages = 257–62  | date = February 2010 | pmid = 19961888 | pmc = 4043136 | doi = 10.1016/j.peptides.2009.11.024 }}</ref> 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.<ref name="pmid23251675">{{cite journal | vauthors = Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L | title = Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population | journal = PLOS One | volume = 7 | issue = 12 | pages = e52026 | year = 2012 | pmid = 23251675 | pmc = 3520898 | doi = 10.1371/journal.pone.0052026 | bibcode = 2012PLoSO...752026A }}</ref>
 
==Function and mechanism of action{{anchor|Cholinergic–dopaminergic reward link}}==
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 [[Adenosine triphosphate|ATP]] production, fat storage, glycogen storage, and short-term heat loss. 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 [[Mechanistic target of rapamycin|mTOR]]/[[P70-S6 Kinase 1|S6K1]] pathway mediating the interaction among ghrelin, [[nesfatin]] and [[endocannabinoid]] gastric systems,<ref name="pmid24732927">{{cite book |vauthors=Folgueira C, Seoane LM, Casanueva FF |year=2014  |chapter=The brain-stomach connection |editor1=Delhanty PJD |editor2=van der Lely AJ |title=How Gut and Brain Control Metabolism |series= Frontiers of Hormone Research |volume= 42 |location= Basel |publisher= Karger |pages= 83–92 |doi= 10.1159/000358316 |isbn= 978-3-318-02638-2 |pmid=24732927}}</ref> and both afferent and efferent vagal signals.
 
Ghrelin and synthetic ghrelin mimetics ([[growth hormone secretagogue]]s) increase body weight and fat mass<ref>{{cite journal | vauthors = Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL | title = Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues | journal = Biochemical and Biophysical Research Communications | volume = 280 | issue = 1 | pages = 132–38  | date = January 2001 | pmid = 11162489 | doi = 10.1006/bbrc.2000.4065 }}</ref><ref>{{cite journal | vauthors = Tschöp M, Smiley DL, Heiman ML | title = Ghrelin induces adiposity in rodents | journal = Nature | volume = 407 | issue = 6806 | pages = 908–13  | date = October 2000 | pmid = 11057670 | doi = 10.1038/35038090 | authorlink1 = Matthias H. Tschöp | bibcode = 2000Natur.407..908T }}</ref><ref name="pmid27095593">{{cite journal |vauthors=Chebani Y, Marion C, Zizzari P, Chettab K, Pastor M, Korostelev M, Geny D, Epelbaum J, Tolle V, Morisset-Lopez S, Pantel J |title=Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite |journal=Science Signaling |volume=9 |issue=424 |pages=ra39 |year=2016 |pmid=27095593 |doi=10.1126/scisignal.aae0374 }}</ref> by triggering receptors in the [[arcuate nucleus]]<ref>{{cite journal | vauthors = Hewson AK, Dickson SL | title = Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats | journal = Journal of Neuroendocrinology | volume = 12 | issue = 11 | pages = 1047–49  | date = November 2000 | pmid = 11069119 | doi = 10.1046/j.1365-2826.2000.00584.x }}</ref><ref>{{cite journal | vauthors = Dickson SL, Leng G, Robinson IC | title = Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons | journal = Neuroscience | volume = 53 | issue = 2 | pages = 303–06  | date = March 1993 | pmid = 8492908 | doi = 10.1016/0306-4522(93)90197-N }}</ref> that include the orexigenic [[neuropeptide Y]] (NPY) and [[agouti-related peptide|agouti-related protein]] (AgRP) neurons.<ref name="pmid14962995">{{cite journal |vauthors=Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, Shen Z, Marsh DJ, Feighner SD, Guan XM, Ye Z, Nargund RP, Smith RG, Van der Ploeg LH, Howard AD, MacNeil DJ, Qian S |title=Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein |journal=Endocrinology |volume=145 |issue=6 |pages=2607–12 |year=2004 |pmid=14962995 |doi=10.1210/en.2003-1596 }}</ref><ref>{{cite journal | vauthors = Dickson SL, Luckman SM | title = 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 | journal = Endocrinology | volume = 138 | issue = 2 | pages = 771–77  | date = February 1997 | pmid = 9003014 | doi = 10.1210/en.138.2.771 }}</ref> Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive.<ref name = "pmid12453894">{{cite journal | vauthors = Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL | title = The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic | journal = Diabetes | volume = 51 | issue = 12 | pages = 3412–19  | date = December 2002 | pmid = 12453894 | doi = 10.2337/diabetes.51.12.3412 }}</ref> Ghrelin reduces the mechanosensitivity of gastric [[Vagus nerve|vagal]] [[afferent nerve fiber|afferents]], so they are less sensitive to gastric distension.<ref name = "pmid17290011" />
 
In addition to its function in energy homeostasis, ghrelin also activates the '''cholinergic–dopaminergic reward link'''<!--This is the target of a section redirect on this topic, so this term is bolded per MOS:BOLD#Other uses.--> in inputs to the [[ventral tegmental area]] and in the [[mesolimbic pathway]],<ref name="pmid16137788"/> a circuit that communicates the hedonic and reinforcing aspects of natural rewards,<ref name="Cholinergic-dopaminergic reward link" /> such as food and addictive drugs such as ethanol.<ref name = "pmid12453894" /><ref>{{cite journal | vauthors = Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA | title = Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward | journal = Addiction Biology | volume = 11 | issue = 1 | pages = 45–54 | date = March 2006 | pmid = 16759336 | doi = 10.1111/j.1369-1600.2006.00002.x }}</ref><ref>{{cite journal | vauthors = Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA | title = Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens | journal = Addiction Biology | volume = 12 | issue = 1 | pages = 6–16  | date = March 2007 | pmid = 17407492 | doi = 10.1111/j.1369-1600.2006.00041.x }}</ref> Ghrelin receptors are located on neurons in this circuit.<ref name="Cholinergic-dopaminergic reward link" /><ref name="NHM-Ghrelin" /> Hypothalamic ghrelin signalling is required for reward from alcohol<ref name = "pmid19564604">{{cite journal | vauthors = Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA | title = Requirement of central ghrelin signaling for alcohol reward | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 27 | pages = 11318–23 | date = July 2009 | pmid = 19564604 | pmc = 2703665 | doi = 10.1073/pnas.0812809106 | bibcode = 2009PNAS..10611318J }}</ref> and palatable/rewarding foods.<ref name = "pmid20477752">{{cite journal | vauthors = Egecioglu E, Jerlhag E, Salomé N, Skibicka KP, Haage D, Bohlooly-Y M, Andersson D, Bjursell M, Perrissoud D, Engel JA, Dickson SL | title = Ghrelin increases intake of rewarding food in rodents | journal = Addiction Biology | volume = 15 | issue = 3 | pages = 304–11 | date = July 2010 | pmid = 20477752 | pmc = 2901520 | doi = 10.1111/j.1369-1600.2010.00216.x }}</ref><ref name = "pmid21309956">{{cite journal | vauthors = Skibicka KP, Hansson C, Egecioglu E, Dickson SL | title = Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression | journal = Addiction Biology | volume = 17 | issue = 1 | pages = 95–107 | date = January 2012 | pmid = 21309956 | pmc = 3298643 | doi = 10.1111/j.1369-1600.2010.00294.x }}</ref>
 
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.<ref name = "pmid11897692">{{cite journal |vauthors=Tolle V, Bassant MH, Zizzari P, Poindessous-Jazat F, Tomasetto C, Epelbaum J, Bluet-Pajot MT |title=Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats |journal=Endocrinology |volume=143 |issue=4 |pages=1353–61 |year=2002 |pmid=11897692 |doi=10.1210/endo.143.4.8712 }}</ref><ref name = "pmid15039149">{{cite journal | vauthors = Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D | title = Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 287 | issue = 2 | pages = E297–304 | date = August 2004 | pmid = 15039149 | doi = 10.1152/ajpendo.00582.2003 }}</ref> Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner.<ref name = "pmid11089570">{{cite journal | vauthors = Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR | title = The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion | journal = Endocrinology | volume = 141 | issue = 11 | pages = 4325–28 | date = November 2000 | pmid = 11089570 | doi = 10.1210/endo.141.11.7873 }}</ref> So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number.<ref name = "pmid12941764">{{cite journal | vauthors = Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ | title = Hyperphagic effects of brainstem ghrelin administration | journal = Diabetes | volume = 52 | issue = 9 | pages = 2260–65 | date = September 2003 | pmid = 12941764 | doi = 10.2337/diabetes.52.9.2260 }}</ref> 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.<ref name = "Schwartz_2000"/>
 
==Blood levels==
Blood levels are in the pmol/l range. Both active and total ghrelin can be measured.<ref name="pmid15863960">{{cite journal | vauthors = Yokota I, Kitamura S, Hosoda H, Kotani Y, Kangawa K | title = Concentration of the n-octanoylated active form of ghrelin in fetal and neonatal circulation | journal = Endocrine Journal | volume = 52 | issue = 2 | pages = 271–76  | date = April 2005 | pmid = 15863960 | doi = 10.1507/endocrj.52.271 }}</ref>  Circulating ghrelin concentrations rise before eating and fall afterward,<ref name = "pmid11897692"/> more strongly in response to protein and carbohydrate than to lipids.<ref name = "Stengel_Tache_2011" />
 
==Ghrelin receptor==
The ghrelin receptor ''GHS-R1a'' (a splice-variant of the [[growth hormone secretagogue receptor]], with the ''GHS-R1b'' 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.<ref name="pmid24651458">{{cite journal | vauthors = Yin Y, Li Y, Zhang W | title = The growth hormone secretagogue receptor: its intracellular signaling and regulation | journal = International Journal of Molecular Sciences | volume = 15 | issue = 3 | pages = 4837–55 | year = 2014 | pmid = 24651458 | pmc = 3975427 | doi = 10.3390/ijms15034837 }}</ref> 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.<ref name = "pmid19896496">{{cite journal | vauthors = Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH | title = Ghrelin in the regulation of body weight and metabolism | journal = Frontiers in Neuroendocrinology | volume = 31 | issue = 1 | pages = 44–60  | date = January 2010 | pmid = 19896496 | doi = 10.1016/j.yfrne.2009.10.008 | authorlink5 = Matthias H. Tschöp }}</ref><ref name = "pmid17290011">{{cite journal | vauthors = Page AJ, Slattery JA, Milte C, Laker R, O'Donnell T, Dorian C, Brierley SM, Blackshaw LA | title = Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 292 | issue = 5 | pages = 1376–84  | date = May 2007 | pmid = 17290011 | doi = 10.1152/ajpgi.00536.2006 }}</ref>
 
==Locations of action==
 
===Gastrointestinal tract===
Ghrelin promotes intestinal cell proliferation and inhibits [[apoptosis]] during inflammatory states and [[oxidative stress]].<ref name = "Waseem_2004">{{cite journal | vauthors = Waseem T, Duxbury M, Ito H, Rocha F, Lautz D, Whang E, Ashley SW, Robinson MK | title = Ghrelin ameliorates TNF-a induced anti-proliferative and pro-apoptotic effects and promotes intestinal epithelial restitution | journal = Journal of the American College of Surgeons | volume = 199 | issue = 3 Supplement | pages = 16 | date = September 2004 | pmid =  | doi = 10.1016/j.jamcollsurg.2004.05.018 }}</ref><ref name = "pmid18291254">{{cite journal | vauthors = Waseem T, Duxbury M, Ito H, Ashley SW, Robinson MK | title = Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways | journal = Surgery | volume = 143 | issue = 3 | pages = 334–42 | date = March 2008 | pmid = 18291254 | pmc = 2278045 | doi = 10.1016/j.surg.2007.09.039 }}</ref> 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]].<ref name = "pmid16697735">{{cite journal | vauthors = Gonzalez-Rey E, Chorny A, Delgado M | title = Therapeutic action of ghrelin in a mouse model of colitis | journal = Gastroenterology | volume = 130 | issue = 6 | pages = 1707–20 | date = May 2006 | pmid = 16697735 | doi = 10.1053/j.gastro.2006.01.041 }}</ref><ref name = "pmid18431503">{{cite journal | vauthors = Wu R, Dong W, Ji Y, Zhou M, Marini CP, Ravikumar TS, Wang P | title = Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion | journal = PLOS One | volume = 3 | issue = 4 | pages = e2026 | year = 2008 | pmid = 18431503 | pmc = 2295264 | doi = 10.1371/journal.pone.0002026 | bibcode = 2008PLoSO...3.2026W }}</ref> Animal models of colitis, ischemia reperfusion, and sepsis-related gut dysfunction have been shown to benefit from therapeutic doses of ghrelin.<ref name = "pmid16697735"/><ref name = "pmid18431503"/> It has also been shown to have regenerative capacity and is beneficial in mucosal injury to the stomach.<ref name = "pmid16423819">{{cite journal | vauthors = Işeri SO, Sener G, Yüksel M, Contuk G, Cetinel S, Gedik N, Yegen BC | title = Ghrelin against alendronate-induced gastric damage in rats | journal = Journal of Endocrinology | volume = 187 | issue = 3 | pages = 399–406 | date = December 2005 | pmid = 16423819 | doi = 10.1677/joe.1.06432 }}</ref>
 
Ghrelin promotes gastrointestinal and pancreatic malignancy.<ref name = "pmid19324542">{{cite journal | vauthors = Waseem T | title = Commentary: Ghrelin's role in gastrointestinal tract cancer | journal = Surgical Oncology | volume = 19 | issue = 1 | pages = e1 | date = March 2010 | pmid = 19324542 | doi = 10.1016/j.suronc.2009.02.014 }}</ref><ref name = "pmid18471933">{{cite journal | vauthors = Waseem T, Ahmad F, Azam M, Qureshi MA | title = Role of ghrelin axis in colorectal cancer: a novel association | journal = Peptides | volume = 29 | issue = 8 | pages = 1369–76 | date = August 2008 | pmid = 18471933 | doi = 10.1016/j.peptides.2008.03.020 }}</ref><ref name = "pmid12951072">{{cite journal | vauthors = Duxbury MS, Waseem T, Ito H, Robinson MK, Zinner MJ, Ashley SW, Whang EE | title = Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness | journal = Biochemical and Biophysical Research Communications | volume = 309 | issue = 2 | pages = 464–68 | date = September 2003 | pmid = 12951072 | doi = 10.1016/j.bbrc.2003.08.024 }}</ref>


Ghrelin exists in an endocrinological inactive (pure peptide) and an active (octanoylated) form (see [[Hexatropin]]). Other side chains than octanoyl were also observed.
===Pancreas===
Ghrelin inhibits glucose-stimulated insulin secretion from beta cells in the pancreatic islets. Ghrelin does this indirectly by promoting local negative feedback mediated by somatostatin from pancreatic delta cells, which selectively express the ghrelin receptor.<ref>{{Cite journal|author1=Michael R. DiGruccio |author2=Alex M. Mawla |author3=Cynthia J. Donaldson |author4=Glyn M. Noguchi |author5=Joan Vaughan |author6=Christopher Cowing-Zitron |author7=Talitha van der Meulen |author8=Mark O. Huising |date=2016-05-02|title=Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets|url=http://www.molmetab.com/article/S2212-8778%2816%2930031-X/abstract?rss=yes|journal=Molecular Metabolism|doi=10.1016/j.molmet.2016.04.007|pmid=27408771|pmc=4921781 |access-date=2016-05-30|volume=5|issue=7 |pages=449–58}}</ref>


==Mechanism of action==
===Glucose metabolism===
The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a gluco-regulatory action.<ref name="pmid24714083">{{cite journal|date=July 2014|title=Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions|journal=European Journal of Endocrinology |volume=171|issue=1|pages=R21–32|doi=10.1530/EJE-14-0183|pmid=24714083|vauthors=Heppner KM, Tong J}}</ref>


Ghrelin has emerged as the first circulating hunger hormone.  Ghrelin and synthetic ghrelin mimetics (the growth hormone secretagogues) increase food intake and increase fat mass<ref>{{cite journal |author= Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL |title= Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. |journal= Biochem Biophys Res Commun |volume=280 |issue=1 |pages=132-138 |year=2001 |pmid=11162489 }}</ref><ref>{{cite journal |author= Tschöp M, Smiley DL, Heiman ML |title= Ghrelin induces adiposity in rodents. |journal= Nature |volume=407 |issue=6806 |pages=908-913 |year=2000}}</ref> by an action exerted at the level of the hypothalamus.  They activate cells in the arcuate nucleus<ref>{{cite journal |author= Hewson AK, Dickson SL.|title= Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. |journal= J Neuroendocrinol. |volume=12  |issue=11 |pages=1047-1049 |year=2000 |pmid=11069119}}</ref><ref>{{cite journal |author= Dickson SL, Leng G, Robinson ICAF. |title= Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons. |journal= Neuroscience|volume=54 |issue= 2 |pages=303-306 |year=1993 |pmid= 8492908 |doi:10.1016/0306-4522(93)90197-N}}</ref> that include the orexigenic neuropeptide Y (NPY) neurones<ref>{{cite journal |author= Dickson SL, Luckman SM. |title= 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. |journal= Endocrinology. |volume=138  |issue=2 |pages=771-777 |year=1997 |pmid=9003014 }}</ref>.  Ghrelin-responsiveness of these neurones is both leptin and insulin sensitive<ref>{{cite journal |author= Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL.|title=The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic. |journal= Diabetes. |volume=51  |issue=12 |pages=3412-3419. year=2002 |pmid=12453894}}</ref>. 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.<ref>{{cite journal |author=Jerlhag E, Egecioglu, E, Dickson SL, Andersson M, Svensson L, Engel JA. |title=Ghrelin Stimulates Locomotor Activity and Accumbal Dopamine-Overflow via Central Cholinergic Systems in Mice: Implications for its Involvement in Brain Reward. |journal=Addiction Biology |volume=11 |issue=1 |pages=45-54 |year=2004 |pmid=16759336}}</ref><ref>{{cite journal |author= Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA. |title= Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens.  |journal= Addiction Biology |volume=12  |pages=6-16 |year=2007| pmid=17407492 }}</ref>
===Nervous system===
<ref>{{cite journal |author= Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL.|title=The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic. |journal= Diabetes. |volume=51  |issue=12 |pages=3412-3419.
|year=2002 |pmid=12453894}}</ref>


==Role in disease==
====Learning and memory====
The [[hippocampus]] plays a significant role in [[neurotrophy]]: the cognitive adaptation to changing environments and the process of learning<ref name = "pmid16491079"/><ref>{{cite journal | vauthors = Atcha Z, Chen WS, Ong AB, Wong FK, Neo A, Browne ER, Witherington J, Pemberton DJ | title = Cognitive enhancing effects of ghrelin receptor agonists | journal = Psychopharmacology | volume = 206 | issue = 3 | pages = 415–27  | date = October 2009 | pmid = 19652956 | doi = 10.1007/s00213-009-1620-6 }}</ref> and it is a potent stimulator of [[growth hormone]].<ref name = "Kojima M, Hosoda H, Date Y, Nakazato M, Chris DeCaney, Matsuo H, Kangawa K 1999 656–60">{{cite journal | vauthors = Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K | title = Ghrelin is a growth-hormone-releasing acylated peptide from stomach | journal = Nature | volume = 402 | issue = 6762 | pages = 656–60  | date = December 1999 | pmid = 10604470 | doi = 10.1038/45230 | bibcode = 1999Natur.402..656K }}</ref>
[[Animal model]]s indicate that ghrelin may enter the [[hippocampus]] from the bloodstream, altering [[Neuron|nerve-cell]] [[Chemical synapse|connections]], and so altering [[learn]]ing and [[memory]].<ref name="pmid24525421">{{cite journal |vauthors=Cahill SP, Hatchard T, Abizaid A, Holahan MR |title=An examination of early neural and cognitive alterations in hippocampal-spatial function of ghrelin receptor-deficient rats |journal=Behavioural Brain Research |volume=264 |issue= |pages=105–15 |year=2014 |pmid=24525421 |doi=10.1016/j.bbr.2014.02.004 }}</ref> 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.<ref name = "pmid16491079">{{cite journal | vauthors = 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 | title = Ghrelin controls hippocampal spine synapse density and memory performance | journal = Nature Neuroscience | volume = 9 | issue = 3 | pages = 381–88 | date = March 2006 | pmid = 16491079 | doi = 10.1038/nn1656 | laysummary = http://www.scienceblog.com/cms/learning_and_memory_stimulated_by_gut_hormone_10083.html | laysource = Science Blog }}</ref> In rodents, X/A-like cells produce ghrelin.<ref name = "pmid22355282">{{cite journal | vauthors = Stengel A, Taché Y | title = Ghrelin – a pleiotropic hormone secreted from endocrine x/a-like cells of the stomach | journal = Frontiers in Neuroscience | volume = 6 | issue =  | pages = 24 | year = 2012 | pmid = 22355282 | pmc = 3280431 | doi = 10.3389/fnins.2012.00024 }}</ref>


Ghrelin levels in the plasma of [[obesity|obese]] individuals are lower than those in leaner individuals.  Those suffering from the eating disorder [[anorexia nervosa]] appear to have high plasma levels of ghrelin.  These findings suggest that ghrelin does not cause anorexia or obesity, rather, ghrelin attempts to correct these disorders. Yildiz and colleagues found that the level of ghrelin increases during the time of day from midnight to dawn in thinner people, suggesting a flaw in the [[circadian rhythm|circadian]] system of obese individuals.<ref>{{cite journal |author=Yildiz B, Suchard M, Wong M, McCann S, Licinio J |title=Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity |journal=Proc Natl Acad Sci U S A |volume=101 |issue=28 |pages=10434-9 |year=2004 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15231997 |pmid=15231997}}</ref> Professor Cappuccio of the University of Warwick has recently discovered that 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, amongst its many other effects, suppresses appetite. However, this study does not explain the low levels of Ghrelin found in the obese population. In the fetuses, it seems that ghrelin is early produced by the lung and promotes its growth.<ref>{{cite journal |author=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.|title=Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia |journal=Pediatr Res |volume=59 |issue=4 |pages=531-7 |year=2006|url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16549524 |pmid=16549524}}</ref>
====Depression====
Ghrelin levels are also high in patients who have cancer-induced [[cachexia]].<ref>{{cite journal |author=Garcia J, Garcia-Touza M, Hijazi R, Taffet G, Epner D, Mann D, Smith R, Cunningham G, Marcelli M |title=Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia |journal=J Clin Endocrinol Metab |volume=90 |issue=5 |pages=2920-6 |year=2005 |url=http://jcem.endojournals.org/cgi/content/full/90/5/2920 |pmid=15713718}}</ref>
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.<ref name = "Spencer_2012">{{cite journal | vauthors = Spencer SJ, Xu L, Clarke MA, Lemus M, Reichenbach A, Geenen B, Kozicz T, Andrews ZB | title = Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress | journal = Biological Psychiatry | volume = 72 | issue = 6 | pages = 457–65 | date = September 2012 | pmid = 22521145 | doi = 10.1016/j.biopsych.2012.03.010 }}</ref> In normal mice, ghrelin can stimulate the [[hypothalamic-pituitary-adrenal axis]], from the [[anterior pituitary]].<ref name = "Spencer_2012"/>


[[Prader-Willi syndrome]] is also characterized by high fasting levels of ghrelin; here the ghrelin levels are associated with high food intake.<ref>{{cite journal |author=Goldstone A, Thomas E, Brynes A, Castroman G, Edwards R, Ghatei M, Frost G, Holland A, Grossman A, Korbonits M, Bloom S, Bell J |title=Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance |journal=J Clin Endocrinol Metab |volume=89 |issue=4 |pages=1718-26 |year=2004 |url=http://jcem.endojournals.org/cgi/content/full/89/4/1718 |pmid=15070936}}</ref>
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 test|forced swim tank]]. Mice with elevated ghrelin swam more than ghrelin deficient mice.<ref name = "pmid18552842">{{cite journal | vauthors = Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM | title = The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress | journal = Nature Neuroscience | volume = 11 | issue = 7 | pages = 752–53 | date = July 2008 | pmid = 18552842 | pmc = 2765052 | doi = 10.1038/nn.2139 }}</ref> 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.


At least one study found that gastric bypass surgery not only reduces the gut's capacity for food, but also dramatically lowers ghrelin levels.<ref>{{cite journal |author=Cummings D, Weigle D, Frayo R, Breen P, Ma M, Dellinger E, Purnell J |title=Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery |journal=N Engl J Med |volume=346 |issue=21 |pages=1623-30 |year=2002 |url=http://content.nejm.org/cgi/content/short/346/21/1623 |pmid=12023994}}</ref>
====Sleep duration====
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.<ref>{{cite journal | vauthors = Taheri S, Lin L, Austin D, Young T, Mignot E | title = Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index | journal = PLOS Medicine | volume = 1 | issue = 3 | pages = e62 | date = December 2004 | pmid = 15602591 | pmc = 535701 | doi = 10.1371/journal.pmed.0010062 }}</ref>


[[Animal model]]s indicate that ghrelin may enter the hippocampus from the [[blood]]stream, enhancing learning and memory.<ref>http://www.scienceblog.com/cms/learning_and_memory_stimulated_by_gut_hormone_10083.html</ref> 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. In rodents, X/A-like cells produce ghrelin.
====Stress-induced fear====
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.<ref name = "pmid24126924">{{cite journal | vauthors = Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA | title = A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear | journal = Molecular Psychiatry | volume = 19 | issue = 12 | pages = 1284–94 | date = December 2014 | pmid = 24126924 | pmc = 3988273 | doi = 10.1038/mp.2013.135 | laysummary = http://web.mit.edu/newsoffice/2013/ghrelin-ptsd-1015.html | laysource = Massachusetts Institute of Technology News }}</ref> Human studies are needed to translate the use of anti-ghrelin treatments to prevent stress-induced psychiatric disorders.


==Relation to obestatin==
====Substantia nigra function====
[[Obestatin]] is a hormone that was found, 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.<ref>{{cite journal |author=Zhang J, Ren P, Avsian-Kretchmer O, Luo C, Rauch R, Klein C, Hsueh A |title=Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake |journal=Science |volume=310 |issue=5750 |pages=996-9 |year=2005 |url=http://www.sciencemag.org/cgi/content/full/310/5750/996 |pmid=16284174}}</ref> The purpose of this mechanism is unknown.
Ghrelin, through its receptor increases the concentration of [[dopamine]] in the [[substantia nigra]].<ref name = "pmid19906954">{{cite journal | vauthors = 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 | title = Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism | journal = The Journal of Neuroscience | volume = 29 | issue = 45 | pages = 14057–65 | date = November 2009 | pmid = 19906954 | pmc = 2845822 | doi = 10.1523/JNEUROSCI.3890-09.2009 }}</ref>


==History and name==
===Reproductive system===
The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999.<ref>{{cite journal |author=Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K |title=Ghrelin is a growth-hormone-releasing acylated peptide from stomach |journal=Nature |volume=402 |issue=6762 |pages=656-60 |year=1999 |url=http://www.nature.com/nature/journal/v402/n6762/full/402656a0.html |pmid=10604470}}</ref> 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''.
Ghrelin has inhibitory effects on [[gonadotropin-releasing hormone]] (GnRH) secretion. It may cause decreased fertility.<ref name = "pmid24173881">{{cite journal | vauthors = Comninos AN, Jayasena CN, Dhillo WS | title = The relationship between gut and adipose hormones, and reproduction | journal = Human Reproduction Update | volume = 20 | issue = 2 | pages = 153–74 | year = 2014 | pmid = 24173881 | doi = 10.1093/humupd/dmt033 }}</ref>
 
===Fetus and neonate===
*Ghrelin is produced early by the fetal lung and promotes lung growth.<ref>{{cite journal | vauthors = Santos M, Bastos P, Gonzaga S, Roriz JM, Baptista MJ, Nogueira-Silva C, Melo-Rocha G, Henriques-Coelho T, Roncon-Albuquerque R, Leite-Moreira AF, De Krijger RR, Tibboel D, Rottier R, Correia-Pinto J | title = Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia | journal = Pediatric Research | volume = 59 | issue = 4 Pt 1 | pages = 531–37  | date = April 2006 | pmid = 16549524 | doi = 10.1203/01.pdr.0000202748.66359.a9 }}</ref>
* Cord blood levels of active and total ghrelin show a correlation between ghrelin levels and birth weight.<ref name="pmid15863960"/>
 
==Anorexia and obesity==
*Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals,<ref name = "pmid11788653">{{cite journal|last1=Shiiya|first1=T|last2=Nakazato|first2=M|last3=Mizuta|first3=M|last4=Date|first4=Y|last5=Mondal|first5=MS|last6=Tanaka|first6=M|last7=Nozoe|first7=S|last8=Hosoda|first8=H|last9=Kangawa|first9=K|last10=Matsukura|first10=S|title=Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion|journal=The Journal of Clinical Endocrinology and Metabolism |date=January 2002|volume=87|issue=1|pages=240–44|doi=10.1210/jcem.87.1.8129|pmid=11788653|accessdate=}}</ref> 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.<ref name = "pmid15070936">{{cite journal | vauthors = Goldstone AP, Thomas EL, Brynes AE, Castroman G, Edwards R, Ghatei MA, Frost G, Holland AJ, Grossman AB, Korbonits M, Bloom SR, Bell JD | title = Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 4 | pages = 1718–26 | date = April 2004 | pmid = 15070936 | doi = 10.1210/jc.2003-031118 }}</ref><ref name = "pmid12466337">{{cite journal | vauthors = DelParigi A, Tschöp M, Heiman ML, Salbe AD, Vozarova B, Sell SM, Bunt JC, Tataranni PA | title = High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 12 | pages = 5461–64 | date = December 2002 | pmid = 12466337 | doi = 10.1210/jc.2002-020871 }}</ref> However, it is also found that consumption of food for pleasure increased peripheral levels of both ghrelin and the [[Endocannabinoids|endocannabinoid]] [[2-Arachidonoylglycerol|2-arachidonoyl-glycerol]] (2-AG) in healthy humans, and this [[Hedonic hunger|hedonic]] eating influences food intake and, ultimately, [[Human body weight|body mass]].<ref>{{Cite journal|last=Monteleone|first=Palmiero|last2=Piscitelli|first2=Fabiana|last3=Scognamiglio|first3=Pasquale|last4=Monteleone|first4=Alessio Maria|last5=Canestrelli|first5=Benedetta|last6=Di Marzo|first6=Vincenzo|last7=Maj|first7=Mario|date=2012-06-01|title=Hedonic eating is associated with increased peripheral levels of ghrelin and the endocannabinoid 2-arachidonoyl-glycerol in healthy humans: a pilot study|journal=The Journal of Clinical Endocrinology and Metabolism|volume=97|issue=6|pages=E917–24|doi=10.1210/jc.2011-3018|issn=1945-7197|pmid=22442280}}</ref>
*Those with [[anorexia nervosa]] have high plasma levels of ghrelin<ref name="pmid24731664">{{cite journal | vauthors = Misra M, Klibanski A | title = Endocrine consequences of anorexia nervosa | journal = The Lancet Diabetes & Endocrinology | volume = 2 | issue = 7 | pages = 581–92  | date = July 2014 | pmid = 24731664 | pmc = 4133106 | doi = 10.1016/S2213-8587(13)70180-3 }}</ref> compared to both the constitutionally thin and normal-weight controls.<ref name="pmid12519838">{{cite journal |vauthors=Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum J, Estour B |title=Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women |journal=The Journal of Clinical Endocrinology and Metabolism |volume=88 |issue=1 |pages=109–16 |year=2003 |pmid=12519838 |doi=10.1210/jc.2002-020645}}</ref><ref name = "pmid17413094">{{cite journal | vauthors = Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F, Bloom SR, Estour B | title = Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin | journal = The American Journal of Clinical Nutrition | volume = 85 | issue = 4 | pages = 967–71 | date = April 2007 | pmid = 17413094 | doi =  10.1093/ajcn/85.4.967| url = http://ajcn.nutrition.org/content/85/4/967.long }}</ref>
*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.<ref name = "pmid15231997">{{cite journal | vauthors = Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J | title = Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 28 | pages = 10434–39 | date = July 2004 | pmid = 15231997 | pmc = 478601 | doi = 10.1073/pnas.0403465101 | bibcode = 2004PNAS..10110434Y }}</ref>
*Ghrelin levels reflect release in a circadian rhythm, which can be interrupted by exposure to light at night.<ref name="pmid24673196">{{cite journal | vauthors = Fonken LK, Nelson RJ | title = The effects of light at night on circadian clocks and metabolism | journal = Endocrine Reviews | volume = 35 | issue = 4 | pages = 648–70  | date = April 2014 | pmid = 24673196 | doi = 10.1210/er.2013-1051 }}</ref>
*Short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes.<ref name = "pmid18517032">{{cite journal | vauthors = Cappuccio FP, Taggart FM, Kandala NB, Currie A, Peile E, Stranges S, Miller MA | title = Meta-analysis of short sleep duration and obesity in children and adults | journal = Sleep | volume = 31 | issue = 5 | pages = 619–26 | date = May 2008 | pmid = 18517032 | pmc = 2398753 | doi =  10.1093/sleep/31.5.619}}</ref>
*Lack of sleep increases ghrelin and decreases leptin, both of which result in increased hunger and obesity.
*Ghrelin levels are high in patients with cancer-induced [[cachexia]].<ref name = "pmid15713718">{{cite journal | vauthors = Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, Smith RG, Cunningham GR, Marcelli M | title = Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 90 | issue = 5 | pages = 2920–26 | date = May 2005 | pmid = 15713718 | doi = 10.1210/jc.2004-1788 }}</ref>
 
==Disease management==


==Anti-obesity vaccine==
===Gastric bypass surgery===
Recently Scripps research scientists have developed an anti-obesity vaccine, which is directed against the hormone ghrelin.<ref>[http://www.scripps.edu/newsandviews/e_20060814/ghrelin.html Scripps.edu] - 'Scripps Research Scientists Successfully Test New Anti-Obesity Vaccine' at [[The Scripps Research Institute]]</ref> <ref>http://www.pnas.org/cgi/content/full/103/35/13226</ref>The vaccine uses the immune system, specifically 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.
[[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.<ref name = "pmid12023994">{{cite journal | vauthors = Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ | title = Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery | journal = The New England Journal of Medicine | volume = 346 | issue = 21 | pages = 1623–30 | date = May 2002 | pmid = 12023994 | doi = 10.1056/NEJMoa012908 }}</ref> 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.<ref name = "pmid12843132">{{cite journal | vauthors = Cummings DE, Shannon MH | title = Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss? | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 7 | pages = 2999–3002 | date = July 2003 | pmid = 12843132 | doi = 10.1210/jc.2003-030705 }}</ref> Bariatric surgeries involving [[vertical-sleeve gastrectomy]] reduce plasma ghrelin levels by about 60% in the long term.<ref name = "pmid20094819">{{cite journal | vauthors = Bohdjalian A, Langer FB, Shakeri-Leidenmühler S, Gfrerer L, Ludvik B, Zacherl J, Prager G | title = Sleeve gastrectomy as sole and definitive bariatric procedure: 5-year results for weight loss and ghrelin | journal = Obesity Surgery | volume = 20 | issue = 5 | pages = 535–40 | date = May 2010 | pmid = 20094819 | doi = 10.1007/s11695-009-0066-6 }}</ref>


==References==
==Aging==
{{Reflist|2}}
Ghrelin plasma concentration increases with age and this may contribute to the tendency for weight gain as people age.<ref>{{cite journal | vauthors = Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS | title = A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans | journal = Diabetes | volume = 50 | issue = 8 | pages = 1714–19 | date = August 2001 | pmid = 11473029 | doi=10.2337/diabetes.50.8.1714}}</ref><ref>{{cite book | last1 = Karasu | first1 = Sylvia R. | last2 = Karasu | first2 = T. Byram | title = The gravity of weight: a clinical guide to weight loss and maintenance | date = 2010 | publisher = American Psychiatric Publishing | location = Washington, DC | isbn = 978-1585623600 | page = 162 | edition = 1st | name-list-format = vanc }}</ref>


==External links==
==Future clinical uses==
* [http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/gi/ghrelin.html Gherlin] at Colorado State University
*Synthetic ghrelin administration for [[cachexia]] of any cause<ref name="pmid24782779">{{cite journal | vauthors = Berardi E, Annibali D, Cassano M, Crippa S, Sampaolesi M | title = Molecular and cell-based therapies for muscle degenerations: a road under construction | journal = Frontiers in Physiology | volume = 5 | issue =  | pages = 119 | year = 2014 | pmid = 24782779 | pmc = 3986550 | doi = 10.3389/fphys.2014.00119 }}</ref> and for hemodialysis patients<ref name="pmid24679014">{{cite journal | vauthors = Ruperto M, Sánchez-Muniz FJ, Barril G | title = A clinical approach to the nutritional care process in protein-energy wasting hemodialysis patients | journal = Nutrición Hospitalaria | volume = 29 | issue = 4 | pages = 735–50 | year = 2014 | pmid = 24679014 | doi = 10.3305/nh.2014.29.4.7222}}</ref> is being investigated.
* [http://www.infobiogen.fr/services/chromcancer/Genes/GhrelinID327.html InfoBiogen.fr] - 'Ghrelin/MTLRP' (motilin-related peptide)
*Ghrelin [[Anticonvulsant|suppresses seizures]] in animal models and is being investigated.<ref name="pmid24705860">{{cite journal | vauthors = Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM | title = Neuropeptides as targets for the development of anticonvulsant drugs | journal = Molecular Neurobiology | volume = 50 | issue = 2 | pages = 626–46  | date = October 2014 | pmid = 24705860 | pmc = 4182642 | doi = 10.1007/s12035-014-8669-x }}</ref>
* [http://neuroendo.org.uk/index.php/content/view/26/11/ NeuroEndo.org.uk] - 'Ghrelin: A newly discovered hormone', Dr. Suzanne L. Dickson, University of Cambridge (June 14, 2005)
*Ghrelin is a gastric [[Prokinetic agent|pro-kinetic]] and may be useful in the treatment of [[gastroparesis]].<ref name="pmid24669936">{{cite journal | vauthors = Hasler WL | title = Emerging drugs for the treatment of gastroparesis | journal = Expert Opinion on Emerging Drugs | volume = 19 | issue = 2 | pages = 261–79  | date = June 2014 | pmid = 24669936 | doi = 10.1517/14728214.2014.899353 }}</ref>
* [http://www.sciencenews.org/articles/20050402/bob9.asp ScienceNews.org] - 'Still Hungry?  Fattening revelations—and new mysteries—about the hunger hormone', Janet Raloff, ''Science News'', vol 167, no 14, p 216 (April 2, 2005)
* [http://www.hungerhormones.com Balancing Hunger Hormones] - Web site reviewing role of ghrelin and leptin in obesity.
* {{MeshName|ghrelin}}


[[Category:Neuropeptides]]
==See also==
[[Category:Obesity]]
* [[Hypothalamic–pituitary–somatic axis]]
[[Category:Endocrinology]]
* [[List of growth hormone secretagogues]]


==Notes==
* {{note|reference_name_A|a}} It is important to note that the full mechanism of ghrelin secretion and reduction has not been fully realized, e.g. "this finding appears to discount gastric distention as a mechanism for ghrelin reduction".<ref>{{cite journal |vauthors=Williams DL, Cummings DE, Grill HJ, Kaplan JM | year = 2003 | title = Meal-Related Ghrelin Suppression Requires Postgastric Feedback | url = | journal = Endocrinology | volume = 144 | issue = 7| pages = 2765–67 | doi = 10.1210/en.2003-0381 | pmid=12810528}}</ref>


==References==
{{Reflist|20em}}
{{Wiktionary}}


[[de:Ghrelin]]
{{Hormones}}
[[dv:ޣްރެލިން]]
{{Neuropeptides}}
[[it:Grelina]]
{{Orexigenics}}
[[ja:グレリン]]
{{GH/IGF-1 axis signaling modulators}}
[[pl:Grelina]]
[[uk:Ґрелін]]


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Ghrelin (pronounced /ˈɡrɛlɪn/), the "hunger hormone", also known as lenomorelin (INN), is a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract[1][2] that functions as a neuropeptide in the central nervous system.[3] Besides regulating appetite, ghrelin also plays a significant role in regulating the distribution and rate of use of energy.[4]

When the stomach is empty, ghrelin is secreted. When the stomach is stretched, secretion stops.a 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.[5]

The receptor for ghrelin, the ghrelin/growth hormone secretagogue receptor (GHS-R), is found on the same cells in the brain as the receptor for leptin, the satiety hormone that has opposite effects from ghrelin.[6] Ghrelin also plays an important role in regulating reward perception in dopamine neurons that link the ventral tegmental area to the nucleus accumbens[7][8] (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.[3][9] 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.

Unlike the case of many other endogenous peptides, ghrelin is able to cross the blood-brain-barrier, giving exogenously-administered ghrelin unique clinical potential.[10]

History and name

Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHS-R) was discovered in 1996[11] and was reported in 1999.[12] 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".[13]

Gene, transcription products, and structure

File:Preproghrelin 1P7X.png
Preproghrelin (green and blue) and ghrelin (green).

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.[14]

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.[15] The non-octanoylated form is desacyl ghrelin. It does not activate the GHS-R receptor but does have other effects: cardiac,[16] anti-ghrelin,[17] appetite stimulation,[18] and inhibition of hepatic glucose output[19] Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor.[20] 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.[21]

Ghrelin cells

Alternative names

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).[22]

Location

Ghrelin cells are found mainly in the stomach[23] and duodenum, but also in the jejunum, lungs, pancreatic islets,[24] gonads, adrenal cortex, placenta, and kidney. It has recently been shown that ghrelin is produced locally in the brain[25]

Features

Ghrelin cells are found in oxyntic glands (20% of cells),[26] pyloric glands, and small intestine. They are ovoid cells with granules.[27] They have gastrin receptors.[28] Some produce nesfatin-1.[29] 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.[30]

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. 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,[31] and both afferent and efferent vagal signals.

Ghrelin and synthetic ghrelin mimetics (growth hormone secretagogues) increase body weight and fat mass[32][33][34] by triggering receptors in the arcuate nucleus[35][36] that include the orexigenic neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons.[37][38] Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive.[39] Ghrelin reduces the mechanosensitivity of gastric vagal afferents, so they are less sensitive to gastric distension.[40]

In addition to its function in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic reward link in inputs to the ventral tegmental area and in the mesolimbic pathway,[7] a circuit that communicates the hedonic and reinforcing aspects of natural rewards,[3] such as food and addictive drugs such as ethanol.[39][41][42] Ghrelin receptors are located on neurons in this circuit.[3][8] Hypothalamic ghrelin signalling is required for reward from alcohol[43] and palatable/rewarding foods.[44][45]

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.[46][47] Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner.[48] So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number.[49] 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.[5]

Blood levels

Blood levels are in the pmol/l range. Both active and total ghrelin can be measured.[50] Circulating ghrelin concentrations rise before eating and fall afterward,[46] more strongly in response to protein and carbohydrate than to lipids.[21]

Ghrelin receptor

The ghrelin receptor GHS-R1a (a splice-variant of the growth hormone secretagogue receptor, with the GHS-R1b 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.[51] 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.[15][40]

Locations of action

Gastrointestinal tract

Ghrelin promotes intestinal cell proliferation and inhibits apoptosis during inflammatory states and oxidative stress.[52][53] 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.[54][55] Animal models of colitis, ischemia reperfusion, and sepsis-related gut dysfunction have been shown to benefit from therapeutic doses of ghrelin.[54][55] It has also been shown to have regenerative capacity and is beneficial in mucosal injury to the stomach.[56]

Ghrelin promotes gastrointestinal and pancreatic malignancy.[57][58][59]

Pancreas

Ghrelin inhibits glucose-stimulated insulin secretion from beta cells in the pancreatic islets. Ghrelin does this indirectly by promoting local negative feedback mediated by somatostatin from pancreatic delta cells, which selectively express the ghrelin receptor.[60]

Glucose metabolism

The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a gluco-regulatory action.[61]

Nervous system

Learning and memory

The hippocampus plays a significant role in neurotrophy: the cognitive adaptation to changing environments and the process of learning[62][63] and it is a potent stimulator of growth hormone.[12] Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, altering nerve-cell connections, and so altering learning and memory.[64] 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.[62] In rodents, X/A-like cells produce ghrelin.[65]

Depression

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.[66] In normal mice, ghrelin can stimulate the hypothalamic-pituitary-adrenal axis, from the anterior pituitary.[66]

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.[67] 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.

Sleep duration

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.[68]

Stress-induced fear

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.[69] Human studies are needed to translate the use of anti-ghrelin treatments to prevent stress-induced psychiatric disorders.

Substantia nigra function

Ghrelin, through its receptor increases the concentration of dopamine in the substantia nigra.[70]

Reproductive system

Ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion. It may cause decreased fertility.[71]

Fetus and neonate

  • Ghrelin is produced early by the fetal lung and promotes lung growth.[72]
  • Cord blood levels of active and total ghrelin show a correlation between ghrelin levels and birth weight.[50]

Anorexia and obesity

  • Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals,[73] 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.[74][75] However, it is also found that consumption of food for pleasure increased peripheral levels of both ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in healthy humans, and this hedonic eating influences food intake and, ultimately, body mass.[76]
  • Those with anorexia nervosa have high plasma levels of ghrelin[77] compared to both the constitutionally thin and normal-weight controls.[78][79]
  • 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.[80]
  • Ghrelin levels reflect release in a circadian rhythm, which can be interrupted by exposure to light at night.[81]
  • Short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes.[82]
  • Lack of sleep increases ghrelin and decreases leptin, both of which result in increased hunger and obesity.
  • Ghrelin levels are high in patients with cancer-induced cachexia.[83]

Disease management

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.[84] 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.[85] Bariatric surgeries involving vertical-sleeve gastrectomy reduce plasma ghrelin levels by about 60% in the long term.[86]

Aging

Ghrelin plasma concentration increases with age and this may contribute to the tendency for weight gain as people age.[87][88]

Future clinical uses

See also

Notes

  • ^a It is important to note that the full mechanism of ghrelin secretion and reduction has not been fully realized, e.g. "this finding appears to discount gastric distention as a mechanism for ghrelin reduction".[93]

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