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'''Ghrelin''' is a [[hormone]] produced by [[P/D1 cell]]s lining the fundus of the human [[stomach]] that stimulate [[appetite]] ([http://www.fasebj.org/cgi/content/full/18/3/439 Bowers, et al]). In rodents, X/A-like cells produce ghrelin. Plasma concentrations of ghrelin increase progressively before meals and decrease after meals. It is considered the counterpart of the hormone [[leptin]], produced by [[adipose tissue]], which suppresses appetite. Ghrelin also stimulates the secretion of [[growth hormone]] from the [[anterior pituitary gland]].
'''Ghrelin''' is a 28 amino-acid pepptide [[hormone]] that is produced by [[P/D1 cell]]s lining the fundus of the human [[stomach]] <ref>[http://www.fasebj.org/cgi/content/full/18/3/439 Bowers C ''et al.'']</ref>. In rodents, similar X/A-like cells in the stomach produce ghrelin. The small intestine, liver, pancreas, kidney, lung, pituitary, hypothalamus, placenta and testes also yield small amounts of ghrelin.<ref name=kirchner2010>Kirchner H ''et al.''(2010) [http://dx.doi.org/10.1152/ajpendo.00191.2009 Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants.] ''Am J Physiol'' </ref> Ghrelin is a potent stimulator of appetite.


Receptors for ghrelin are expressed in several areas of the central nervous system, but at particularly high densities by neurons in the [[arcuate nucleus]] and the [[ventromedial hypothalamus]]. The ghrelin receptor is a G-protein coupled membrane receptor, formerly known as the GHS receptor (growth hormone secretagogue receptor). There is also evidence that ghrelin may also be made by a small population of neurons in the arcuate nucleus.
The discovery of ghrelin was reported by Kojima ''et al.'' in 1999. <ref>Kojima M ''et al.'' (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach  ''Nature'' 402:656-60 PMID 10604470</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''.  


==Forms==
Originally identified as the endogenous ligand for the 'growth hormone secretagogue'(GHS) receptor, ghrelin was first thought to be mainly involved in the regulation of [[growth hormone]] secretion from the [[anterior pituitary gland]]; however, it was soon found also to be a potent orexigen (appetite stimulant) &mdash; sometimes referred to as the 'hunger hormone'. In humans, plasma concentrations of ghrelin increase progressively before meals and decrease after meals.  Ghrelin is the only known orexigenic hormone produced by the gut,<ref name=hameed2009>Hameed S ''et al.'' (2009). [http://dx.doi.org/10.1111/j.1601-0825.2008.01492.x Gut hormones and appetite control] ''Oral Diseases'' 15:18-26.</ref> and the only known orexigenic molecule in the blood circulation.<ref name=kirchner2010/> In some respects it can be considered as a counterpart of the hormone [[leptin]]; leptin, a hormone produced by [[adipose tissue]], suppresses appetite (an anorexigen).


Ghrelin exists in an inactive (pure peptide) and an active (octanoylated) form (see [[Hexatropin]]). Other side chains than octanoyl were also observed.
==Receptors==
Receptors for ghrelin (G-protein coupled membrane receptors, variously called GHS receptors or ghrelin receptors) are expressed in the anterior pituitary and in several areas of the central nervous system. Receptor expression is at particularly high densities in neurons of the [[arcuate nucleus]] and the [[ventromedial nucleus]] of the [[hypothalamus]]. There is also evidence that ghrelin may also be made by a small population of neurons in the arcuate nucleus.


==Role in disease==
In rats and mice, systemic or central application of ghrelin increases food intake and increases fat mass (adiposity) <ref>{{cite journal |author=Lall S ''et al.'' |title=Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues |journal=Biochem Biophys Res Commun |volume=280 |pages=132–8 |year=2001 |pmid=11162489  }}</ref><ref>{{cite journal |author=Tschöp M ''et al.'' |title=Ghrelin induces adiposity in rodents |journal=Nature |volume=407  |pages=908–13 |year=2000 }}</ref> as a result of its actions at the hypothalamus. Sustemic injections of ghrelin 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  |pages=1047–9 |year=2000 |pmid=11069119 }}</ref><ref>{{cite journal |author=Dickson SL ''et al.''|title=Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons |journal=Neuroscience|volume=54  |pages=303–6 |year=1993 |pmid=8492908 |doi=10.1016/0306-4522(93)90197-N}}</ref> including the orexigenic neuropeptide Y (NPY) neurons, as well as the neuroendocrine neurons that secrete [[growth-hormone releasing hormone]].<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  |pages=771–7 |year=1997 |pmid=9003014  }}</ref> Ghrelin-responsiveness of these neurones is both leptin- and insulin-sensitive, tending to have a suppressive effect.<ref>{{cite journal |author=Hewson AK ''et al.''|title=The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic |journal=Diabetes |volume=51  |pages=3412–9. pmid=12453894 |year=2002}}</ref> Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a neural circuit that communicates the hedonic and reinforcing aspects of natural rewards, including food, as well as of addictive drugs, such as alcohol.<ref>{{cite journal |author=Jerlhag E ''et al.''|title=Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: Implications for its involvement in brain reward |journal=Addiction Biol |volume=11  |pages=45–54 |year=2004 |pmid=16759336 |doi=10.1111/j.1369-1600.2006.00002.x}}</ref><ref>{{cite journal |author= Jerlhag E ''et al.'' |title= Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens  |journal= Addiction Biol |volume=12  |pages=6–16 |year=2007| pmid=17407492 }}</ref>
<ref>{{cite journal |author= Hewson AK ''et al.''|title=The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic |journal= Diabetes |volume=51  |pages=3412–9
|year=2002 |pmid=12453894 |doi=10.2337/diabetes.51.12.3412 }}</ref>{{Image|Ghrelinactions2.jpg |right|350px|Schematic of ghrelin actions in the arcuate nucleus}}


Ghrelin levels in the plasma of [[obesity|obese]] individuals are lower than those in leaner individuals.  Yildiz ''et al'' (2004) 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. 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.
Ghrelin exists in both an inactive (pure peptide) and an active (octanoylated) form (see [[Hexatropin]]).  


Those suffering from the eating disorder [[anorexia nervosa]] appear to have high plasma levels of ghrelin. Ghrelin levels are also high in patients who have cancer-induced [[cachexia]] (Garcia ''et al'', 2005).
The physiological importance of ghrelin as a regulator of growth hormone secretion is still unclear, but there is concern that the ability of ghrelin agonists to stimulate growth hormone secretion might lead to abuse by athletes. <ref>Segura J ''et al.'' (2009) Growth hormone in sport: beyond Beijing 2008 ''Ther Drug Monit'' 31:3-13 PMID 19155963</ref>
 
There is some evidence that defective ghrelin signalling result in short stature in humans.<ref>
Prader Willi Syndrome is another example of high levels of Ghrelin, but here the ghrelin level are associated with high food intake.
Pantel J ''et al.'' (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature ''J Clin Invest'' 116:760-8 PMID 16511605</ref> There is also evidence that altered ghrelin signalling might be a factor that contributes to obesity<ref>Leskelä P ''et al.'' (2009) Fasting plasma total ghrelin concentrations in monozygotic twins discordant for obesity. ''Metabolism'' 58:174-9 PMID 19154949</ref>. <ref>Yildiz BO ''et al.'' (2004) Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity ''Proc Natl Acad Sci U S A'' 101:10434-9  PMID 15231997.</ref>Clinically, the ability of ghrelin to stimulate appetite indicates its potential value in the treatment of [[cachexia]].<ref>DeBoer MD (2008) Emergence of ghrelin as a treatment for cachexia syndromes.''Nutrition'' 24:806-14</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 (Cummings ''et al'', 2002).
 
[[Animal model]]s indicate that ghrelin may enter the hippocampus from the [[blood]]stream, enhancing learning and memory [http://www.scienceblog.com/cms/learning_and_memory_stimulated_by_gut_hormone_10083.html].  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.


==Relation to obestatin==
==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 (Zhang ''et al'' 2005).  The purpose of this mechanism is unknown.
[[Obestatin]] is a closely related hormone that was reported, in late 2005, to ''decrease'' appetite.  Both obestatin and ghrelin are encoded by the same [[gene]]; the gene's product is cleaved to yield the two peptide hormones <ref>* Zhang JV ''et al.'' (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.  ''[[Science (journal)|Science]]'' 310:996-999.  PMID 16284174</ref>.  The physiological significance of this is unknown.


==History and name==


The discovery of ghrelin was reported by Masayasu Kojima ''et al'' in [[1999]].  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''.
==References==
<references/>


==Anti-Obesity Vaccine==
Recently Scripps research scientists have developed an anti-obesity vaccine, which is directed against the hormone ghrelin. 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.
==References==


* Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, Smith RG, Cunningham GR, Marcelli M.  "Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia."  ''J Clin Endocrinol Metab'' 2005;90:2920-6. PMID 15713718.
* Cummings DE, ''et al.'' (2002) [http://content.nejm.org/cgi/content/short/346/21/1623 Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery].  ''[[New England Journal of Medicine]]'' 346:1623-1630.[[Category:Suggestion Bot Tag]]
* Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. "Ghrelin is a growth-hormone-releasing acylated peptide from stomach."  ''[[Nature (journal)|Nature]]'' 1999;402:656-60.  PMID 10604470.
* Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J. "Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity."  ''[[Proceedings of the National Academy of Sciences|Proc Natl Acad Sci U S A]]'' 2004;101:10434-9.  PMID 15231997.
* Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. "[http://content.nejm.org/cgi/content/short/346/21/1623 Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery]." ''[[New England Journal of Medicine]]'' 2002;346:1623-1630.
* Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJW.  "Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake."  ''[[Science (journal)|Science]]'' 2005;310:996-999.  PMID 16284174.

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Ghrelin is a 28 amino-acid pepptide hormone that is produced by P/D1 cells lining the fundus of the human stomach [1]. In rodents, similar X/A-like cells in the stomach produce ghrelin. The small intestine, liver, pancreas, kidney, lung, pituitary, hypothalamus, placenta and testes also yield small amounts of ghrelin.[2] Ghrelin is a potent stimulator of appetite.

The discovery of ghrelin was reported by Kojima et al. in 1999. [3] 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.

Originally identified as the endogenous ligand for the 'growth hormone secretagogue'(GHS) receptor, ghrelin was first thought to be mainly involved in the regulation of growth hormone secretion from the anterior pituitary gland; however, it was soon found also to be a potent orexigen (appetite stimulant) — sometimes referred to as the 'hunger hormone'. In humans, plasma concentrations of ghrelin increase progressively before meals and decrease after meals. Ghrelin is the only known orexigenic hormone produced by the gut,[4] and the only known orexigenic molecule in the blood circulation.[2] In some respects it can be considered as a counterpart of the hormone leptin; leptin, a hormone produced by adipose tissue, suppresses appetite (an anorexigen).

Receptors

Receptors for ghrelin (G-protein coupled membrane receptors, variously called GHS receptors or ghrelin receptors) are expressed in the anterior pituitary and in several areas of the central nervous system. Receptor expression is at particularly high densities in neurons of the arcuate nucleus and the ventromedial nucleus of the hypothalamus. There is also evidence that ghrelin may also be made by a small population of neurons in the arcuate nucleus.

In rats and mice, systemic or central application of ghrelin increases food intake and increases fat mass (adiposity) [5][6] as a result of its actions at the hypothalamus. Sustemic injections of ghrelin activate cells in the arcuate nucleus[7][8] including the orexigenic neuropeptide Y (NPY) neurons, as well as the neuroendocrine neurons that secrete growth-hormone releasing hormone.[9] Ghrelin-responsiveness of these neurones is both leptin- and insulin-sensitive, tending to have a suppressive effect.[10] Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a neural circuit that communicates the hedonic and reinforcing aspects of natural rewards, including food, as well as of addictive drugs, such as alcohol.[11][12]

[13]

Schematic of ghrelin actions in the arcuate nucleus

Ghrelin exists in both an inactive (pure peptide) and an active (octanoylated) form (see Hexatropin).

The physiological importance of ghrelin as a regulator of growth hormone secretion is still unclear, but there is concern that the ability of ghrelin agonists to stimulate growth hormone secretion might lead to abuse by athletes. [14] There is some evidence that defective ghrelin signalling result in short stature in humans.[15] There is also evidence that altered ghrelin signalling might be a factor that contributes to obesity[16]. [17]Clinically, the ability of ghrelin to stimulate appetite indicates its potential value in the treatment of cachexia.[18]

Relation to obestatin

Obestatin is a closely related hormone that was reported, in late 2005, to decrease appetite. Both obestatin and ghrelin are encoded by the same gene; the gene's product is cleaved to yield the two peptide hormones [19]. The physiological significance of this is unknown.


References

  1. ↑ Bowers C et al.
  2. ↑ 2.0 2.1 Kirchner H et al.(2010) Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants. Am J Physiol
  3. ↑ Kojima M et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach Nature 402:656-60 PMID 10604470
  4. ↑ Hameed S et al. (2009). Gut hormones and appetite control Oral Diseases 15:18-26.
  5. ↑ Lall S et al. (2001). "Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues". Biochem Biophys Res Commun 280: 132–8. PMID 11162489.
  6. ↑ Tschöp M et al. (2000). "Ghrelin induces adiposity in rodents". Nature 407: 908–13.
  7. ↑ Hewson AK, Dickson SL (2000). "Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats". J Neuroendocrinol 12: 1047–9. PMID 11069119.
  8. ↑ Dickson SL et al. (1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience 54: 303–6. DOI:10.1016/0306-4522(93)90197-N. PMID 8492908. Research Blogging.
  9. ↑ Dickson SL, Luckman SM. (1997). "Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6". Endocrinology 138: 771–7. PMID 9003014.
  10. ↑ Hewson AK et al. (2002). "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes 51: 3412–9. pmid=12453894.
  11. ↑ Jerlhag E et al. (2004). "Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: Implications for its involvement in brain reward". Addiction Biol 11: 45–54. DOI:10.1111/j.1369-1600.2006.00002.x. PMID 16759336. Research Blogging.
  12. ↑ Jerlhag E et al. (2007). "Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens". Addiction Biol 12: 6–16. PMID 17407492.
  13. ↑ Hewson AK et al. (2002). "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes 51: 3412–9. DOI:10.2337/diabetes.51.12.3412. PMID 12453894. Research Blogging.
  14. ↑ Segura J et al. (2009) Growth hormone in sport: beyond Beijing 2008 Ther Drug Monit 31:3-13 PMID 19155963
  15. ↑ Pantel J et al. (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature J Clin Invest 116:760-8 PMID 16511605
  16. ↑ Leskelä P et al. (2009) Fasting plasma total ghrelin concentrations in monozygotic twins discordant for obesity. Metabolism 58:174-9 PMID 19154949
  17. ↑ Yildiz BO et al. (2004) Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity Proc Natl Acad Sci U S A 101:10434-9 PMID 15231997.
  18. ↑ DeBoer MD (2008) Emergence of ghrelin as a treatment for cachexia syndromes.Nutrition 24:806-14
  19. ↑ * Zhang JV et al. (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310:996-999. PMID 16284174


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