Ghrelin 768527 226143234 2008-07-17T00:39:06Z Someguy1221 3315180 /* External links */ remotely better {{PBB|geneid=51738}} '''Ghrelin''' is a [[hormone]] produced mainly by [[P/D1 cell]]s lining the [[fundus (stomach)|fundus]] of the human [[stomach]] and epsilon cells of the [[pancreas]] that stimulates [[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 |doi= 10.1016/j.regpep.2004.08.038}}</ref> In some [[bariatrics|bariatric]] procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur. 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 |accessdate=2007-06-01 |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]]. ==Forms== Ghrelin exists in an endocrinological inactive (pure peptide) and an active (octanoylated) form (see [[Hexatropin]]). Other side chains than octanoyl were also observed. ==Mechanism of action== 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 |doi= 10.1006/bbrc.2000.4065}}</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 |doi= 10.1038/35038090}}</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 |doi= 10.1046/j.1365-2826.2000.00584.x}}</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 |doi= 10.1210/en.138.2.771}}</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 |doi= 10.2337/diabetes.51.12.3412|year=2002}}</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 |doi=10.1111/j.1369-1600.2006.00002.x}}</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 |doi= 10.1111/j.1369-1600.2006.00041.x}}</ref> <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 |doi= 10.2337/diabetes.51.12.3412 }}</ref> ==Role in disease== Ghrelin levels in the plasma of [[obesity|obese]] individuals are lower than those in leaner individuals[http://content.nejm.org/cgi/content/abstract/346/21/1623] except in the case of [[Prader-Willi syndrome]]-induced obesity. Those suffering from the eating disorder [[anorexia nervosa]] have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls[http://www.ajcn.org/cgi/content/abstract/85/4/967]. These findings suggest that ghrelin plays a role in both anorexia and obesity. 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 |doi=10.1073/pnas.0403465101}}</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. 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 |doi=10.1203/01.pdr.0000202748.66359.a9}}</ref> 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 |doi=10.1210/jc.2004-1788}}</ref> [[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 |doi=10.1210/jc.2003-031118}}</ref> At least one study found that gastric bypass surgery not only reduces the gut's capacity for food, but also dramatically lowers ghrelin levels compared to both lean controls and those who lost weight through dieting alone.<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 |doi=10.1056/NEJMoa012908}}</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 Learning and memory stimulated by gut hormone | Science Blog<!-- Bot generated title -->]</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. ==Relation to obestatin== [[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 |doi=10.1126/science.1117255}}</ref> The purpose of this mechanism is unknown. ==History and name== 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 |doi=10.1038/45230}}</ref> The name is based on its role as a ''growth hormone-releasing peptide'', with reference to the [[Proto-Indo-European language|Proto-Indo-European]] root ''ghre'', meaning ''to grow''. ==Anti-obesity vaccine== 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 From the Cover: Vaccination against weight gain - Zorrilla et al. 103 (35): 13226 - Proceedings of the National Academy of Sciences<!-- Bot generated title -->]</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. ==Antidepressant effect== A study appearing in the journal Nature Neuroscience ([[June 15]], [[2008]] online) suggests that the hormone might help defend against symptoms of stress-induced depression and anxiety.<ref>{{cite journal |author=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=J Nat Neurosci. |year=2008 |date=June 15 |pmid=18552842 |doi=10.1038/nn.2139 |volume=11 |pages=752 |unused_data=|PubMed - as supplied by publisher}}</ref> To test whether ghrelin could regulate depressive symptoms brought on by chronic stress, the researchers subjected mice to daily bouts of social stress, using a standard laboratory technique that induces stress by exposing normal mice to very aggressive “bully” mice. Such animals have been shown to be good models for studying depression in humans. The researchers stressed both wild-type mice and altered mice that were unable to respond to ghrelin. They found that after experiencing stress, both types of mice had significantly elevated levels of ghrelin that persisted at least four weeks after their last defeat encounter. The altered mice, however, displayed significantly greater social avoidance than their wild-type counterparts, indicating an exacerbation of depression-like symptoms. They also ate less than the wild-type mice.<ref>[http://newswise.com/articles/view/541725/ Newswise: Hunger Hormone Increases During Stress, May Have Antidepressant Effect] Retrieved on June 18, 2008.</ref> ==References== {{Reflist|2}} ==External links== * [http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/gi/ghrelin.html Ghrelin] at [[Colorado State University]] * [http://www.infobiogen.fr/services/chromcancer/Genes/GhrelinID327.html InfoBiogen.fr] - 'Ghrelin/MTLRP' (motilin-related peptide) * [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) * [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. * [http://www.msnbc.msn.com/id/25680029/ Feeling Hungry Can Make You Happy] * {{MeshName|ghrelin}} [[Category:Neuropeptides]] [[Category:Obesity]] [[de:Ghrelin]] [[dv:ޣްރެލިން]] [[fr:Ghréline]] [[it:Grelina]] [[nl:Ghreline]] [[ja:グレリン]] [[pl:Grelina]] [[fi:Greliini]] [[uk:Ґрелін]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = no }}