Ghrelin: Wikis

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Ghrelin/obestatin preprohormone
Identifiers
Symbols GHRL; MTLRP; ghrelin; obestatin
External IDs OMIM605353 MGI1930008 HomoloGene9487 GeneCards: GHRL Gene
Orthologs
Species Human Mouse
Entrez 51738 58991
Ensembl ENSG00000157017 ENSMUSG00000064177
UniProt Q9UBU3 Q9EQX0
RefSeq (mRNA) NM_016362 NM_021488
RefSeq (protein) NP_057446 NP_067463
Location (UCSC) Chr 3:
10.3 - 10.31 Mb
Chr 6:
113.68 - 113.69 Mb
PubMed search [1] [2]

Ghrelin is a hormone produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger.[1] 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. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.

Ghrelin is also produced in the hypothalamic arcuate nucleus, where it stimulates the secretion of growth hormone from the anterior pituitary gland.[2]. 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 plays a significant role in neurotrophy, particularly in the hippocampus, and is essential for cognitive adaptation to changing environments and the process of learning.[3][4] Recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.

Contents

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[5][6] by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus[7][8] that include the orexigenic neuropeptide Y (NPY) neurons.[9] Ghrelin-responsiveness of these neurones is both leptin- and insulin-sensitive.[10] 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.[11][12] [13]

Roles of Ghrelin

Lung Development
In foetuses, it seems that ghrelin is early produced by the lung and promotes its growth.[14]
Learning and Memory
Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, altering nerve-cell connections, and so enhancing learning and memory. It is suggested that learning may be best during the day and when the stomach is empty, since ghrelin levels are higher at these times. The team of the Yale School of Medicine also noted that a similar effect for human neural-physiology is quite plausible.[15] In rodents, X/A-like cells produce ghrelin.
Stress-Induced Depression
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.[16] 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.[17]
Sleep-Duration
A study [18] appearing in the journal PLoS Medicine suggests that short sleep duration is associated with high levels of ghrelin and obesity; ghrelin appears to be a factor contributing to the short sleep duration and obesity. Scientists have uncovered an inverse relationship between the hours of sleep and blood plasma concentrations of ghrelin; as the hours of sleep increase, ghrelin concentrations were considerably lower, thereby potentially reducing appetite and avoiding potential obesity.

Role in Disease

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals[19] 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.[20] 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 system of obese individuals.[21] 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, among its many other effects, suppresses appetite.

Ghrelin levels are also high in patients that have cancer-induced cachexia.[22]

Prader-Willi syndrome is also characterized by high fasting levels of ghrelin; here the ghrelin levels are associated with high food intake.[23]

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 that lost weight through dieting alone.[24]

Ghrelin through its receptor increases the concentration of dopamine in the substantia nigra, a region of the brain where dopamine cell degeneration leads to Parkinson's disease. Hence ghrelin may find application in slowing down the onset of Parkinson's disease.[25]

Role in the gastrointestinal tract

Ghrelin has been proposed as a hormone which promotes intestinal cell proliferation and inhibits its apoptosis during inflammatory states and oxidative stress.[26][27] It also suppresses the 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.[28][29] In fact, animal models of colitis, ischemia re-perfusion and sepsis related gut dysfunction have been shown to be benefited with therapeutic doses of ghrelin.[28][29] It has also been shown to have regenerative capacity and is beneficial in case of mucosal injury to the stomach.[30] Ghrelin also enhances the motility of gastrointestinal tract like does motilin. Ghrelin also appears to promote gastrointestinal and pancreatic malignancy.[31][32][33]

Relation to obestatin

Obestatin is a putative hormone that was described, 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.[34] The purpose of this mechanism is unknown.

History and name

The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999.[35] 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. The name can also be viewed as an interesting (and incidental) pun, too, as the initial letters of the phrase growth hormone-releasing give us "ghre" with "lin" as a usual suffix for some hormones.

Anti-obesity vaccine

Recently, Scripps research scientists have developed an anti-obesity vaccine, which is directed against the hormone ghrelin.[36][37] 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

  1. ^ Inui A, Asakawa A, Bowers CY, et al. (2004). "Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ". FASEB J. 18 (3): 439–56. doi:10.1096/fj.03-0641rev. PMID 15003990. http://www.fasebj.org/cgi/content/full/18/3/439.  
  2. ^ Mondal, M.S., Date, Y., Yamaguchi, H., Toshinai, K., Tsuruta, T., Kangawa, K., Nakazato, M. (2005). "Identification of ghrelin and its receptor in neurons of the rat arcuate nucleus". Regul. Pept 126 (1-2): 55–59. doi:10.1016/j.regpep.2004.08.038. PMID 15620414.  
  3. ^ "Hunger hormone tied to learning". http://www.the-scientist.com/news/display/23132/. Retrieved 2007-06-01.   at The Scientist
  4. ^ Atcha Z, Chen WS, Ong AB, Wong FK, Neo A, Browne ER, Witherington J, Pemberton DJ. (2009). Cognitive enhancing effects of ghrelin receptor agonists. Psychopharmacology (Berl). 206(3):415-27. PMID 19652956
  5. ^ Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL (2001). "Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues". Biochem Biophys Res Commun 280 (1): 132–138. doi:10.1006/bbrc.2000.4065. PMID 11162489.  
  6. ^ Tschöp M, Smiley DL, Heiman ML (2000). "Ghrelin induces adiposity in rodents". Nature 407 (6806): 908–913. doi:10.1038/35038090. PMID 11057670.  
  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 (11): 1047–1049. doi:10.1046/j.1365-2826.2000.00584.x. PMID 11069119.  
  8. ^ Dickson SL, Leng G, Robinson ICAF. (1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience 54 (2): 303–306. doi:10.1016/0306-4522(93)90197-N. PMID 8492908.  
  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 (2): 771–777. doi:10.1210/en.138.2.771. PMID 9003014.  
  10. ^ Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL. (2002). "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes. 51 (12): 3412–3419. pmid=12453894. doi:10.2337/diabetes.51.12.3412.  
  11. ^ Jerlhag E, Egecioglu, E, Dickson SL, Andersson M, Svensson L, Engel JA. (2004). "Ghrelin Stimulates Locomotor Activity and Accumbal Dopamine-Overflow via Central Cholinergic Systems in Mice: Implications for its Involvement in Brain Reward". Addiction Biology 11 (1): 45–54. doi:10.1111/j.1369-1600.2006.00002.x. PMID 16759336.  
  12. ^ Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA. (2007). "Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens". Addiction Biology 12 (1): 6–16. doi:10.1111/j.1369-1600.2006.00041.x. PMID 17407492.  
  13. ^ Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL. (2002). "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes. 51 (12): 3412–3419.. doi:10.2337/diabetes.51.12.3412. PMID 12453894.  
  14. ^ Santos M, Bastos P, Gonzaga S, Roriz JM, Baptista MJ, Nogueira-Silva C, Melo-Rocha G, Henriques-Coelho T, Roncon-Albuquerque R Jr, Leite-Moreira AF, De Krijger RR, Tibboel D, Rottier R, Correia-Pinto J. (2006). "Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia". Pediatr Res 59 (4 Pt 1): 531–7. doi:10.1203/01.pdr.0000202748.66359.a9. PMID 16549524. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0031-3998&volume=59&issue=4&spage=531.  
  15. ^ Learning and memory stimulated by gut hormone | Science Blog
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  17. ^ Newswise: Hunger Hormone Increases During Stress, May Have Antidepressant Effect Retrieved on June 18, 2008.
  18. ^ Taheri S, Lin L, Austin D, Young T, Mignot E (December 2004). "Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index". PLoS Med. 1 (3): e62. doi:10.1371/journal.pmed.0010062. PMID 15602591. PMC 535701. http://dx.plos.org/10.1371/journal.pmed.0010062.  
  19. ^ Cummings DE, Weigle DS, Frayo RS, et al. (May 2002). "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery". N. Engl. J. Med. 346 (21): 1623–30. doi:10.1056/NEJMoa012908. PMID 12023994. http://content.nejm.org/cgi/content/abstract/346/21/1623.  
  20. ^ Germain N, Galusca B, Le Roux CW, et al. (1 April 2007). "Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin". Am. J. Clin. Nutr. 85 (4): 967–71. PMID 17413094. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=17413094.  
  21. ^ Yildiz B, Suchard M, Wong M, McCann S, Licinio J (2004). "Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity". Proc Natl Acad Sci USA 101 (28): 10434–9. doi:10.1073/pnas.0403465101. PMID 15231997. PMC 478601. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15231997.  
  22. ^ Garcia J, Garcia-Touza M, Hijazi R, Taffet G, Epner D, Mann D, Smith R, Cunningham G, Marcelli M (2005). "Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia". J Clin Endocrinol Metab 90 (5): 2920–6. doi:10.1210/jc.2004-1788. PMID 15713718. http://jcem.endojournals.org/cgi/content/full/90/5/2920.  
  23. ^ Goldstone A, Thomas E, Brynes A, Castroman G, Edwards R, Ghatei M, Frost G, Holland A, Grossman A, Korbonits M, Bloom S, Bell J (2004). "Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance". J Clin Endocrinol Metab 89 (4): 1718–26. doi:10.1210/jc.2003-031118. PMID 15070936. http://jcem.endojournals.org/cgi/content/full/89/4/1718.  
  24. ^ Cummings D, Weigle D, Frayo R, Breen P, Ma M, Dellinger E, Purnell J (2002). "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery". N Engl J Med 346 (21): 1623–30. doi:10.1056/NEJMoa012908. PMID 12023994. http://content.nejm.org/cgi/content/short/346/21/1623.  
  25. ^ Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J, Elsworth JD, Savitt JM, DiMarchi R, Tschoep M, Roth RH, Gao XB, Horvath TL (November 2009). "Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism". J. Neurosci. 29 (45): 14057–65. doi:10.1523/JNEUROSCI.3890-09.2009. PMID 19906954.  
  26. ^ Waseem T, Duxbury M, Ito H, Rocha F, Lautz D, Whang E, Ashley SW, Robinson MK (September 2004). "Ghrelin ameliorates TNF-a induced anti-proliferative and pro-apoptotic effects and promotes intestinal epithelial restitution". Journal of the American College of Surgeons 199 (3 Supplement): 16. doi:10.1016/j.jamcollsurg.2004.05.018.  
  27. ^ Waseem T, Duxbury M, Ito H, Ashley SW, Robinson MK (March 2008). "Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways". Surgery 143 (3): 334–42. doi:10.1016/j.surg.2007.09.039. PMID 18291254.  
  28. ^ a b Gonzalez-Rey E, Chorny A, Delgado M (May 2006). "Therapeutic action of ghrelin in a mouse model of colitis". Gastroenterology 130 (6): 1707–20. doi:10.1053/j.gastro.2006.01.041. PMID 16697735.  
  29. ^ a b Wu R, Dong W, Ji Y, Zhou M, Marini CP, Ravikumar TS, Wang P (2008). "Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion". PLoS ONE 3 (4): e2026. doi:10.1371/journal.pone.0002026. PMID 18431503.  
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  34. ^ Zhang J, Ren P, Avsian-Kretchmer O, Luo C, Rauch R, Klein C, Hsueh A (2005). "Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake". Science 310 (5750): 996–9. doi:10.1126/science.1117255. PMID 16284174. http://www.sciencemag.org/cgi/content/full/310/5750/996.  
  35. ^ Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999). "Ghrelin is a growth-hormone-releasing acylated peptide from stomach". Nature 402 (6762): 656–60. doi:10.1038/45230. PMID 10604470. http://www.nature.com/nature/journal/v402/n6762/full/402656a0.html.  
  36. ^ Scripps.edu - 'Scripps Research Scientists Successfully Test New Anti-Obesity Vaccine' at The Scripps Research Institute
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