Ghrelin

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 appetite. [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] 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. [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] . 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. [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] Recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.Fact|date=August 2008

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 [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] [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] by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus [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] [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] that include the orexigenic neuropeptide Y (NPY) neurones [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] . Ghrelin-responsiveness of these neurones is both leptin and insulin sensitive [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] . 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. [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] [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] [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]

Roles of Ghrelin

;Lung Development:In the fetuses, it seems that ghrelin is early produced by the lung and promotes its growth. [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]

;Learning and Memory:Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, enhancing learning and memory. [ [http://www.scienceblog.com/cms/learning_and_memory_stimulated_by_gut_hormone_10083.html Learning and memory stimulated by gut hormone | Science Blog ] ] 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 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. [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] 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. [ [http://newswise.com/articles/view/541725/ Newswise: Hunger Hormone Increases During Stress, May Have Antidepressant Effect] Retrieved on June 18, 2008.]

Role in Disease

Ghrelin levels in the plasma of 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 system of obese individuals. [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] 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 levels are also high in patients who have cancer-induced cachexia. [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]

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

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. [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]

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. [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] The purpose of this mechanism is unknown.

History and name

The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999. [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] 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. [ [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] [ [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 ] ] 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

External links

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* [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)

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