Ghrelin
From DrugPedia: A Wikipedia for Drug discovery
[edit] Description
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.<ref>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:. PMID 15003990.</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. 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.<ref>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: 55–59. doi:.</ref>. 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.<ref>Template:Cite web 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 kinases including Akt.Template:Fact
[edit] Forms
Ghrelin exists in an endocrinological inactive (pure peptide) and an active (octanoylated) form (see Hexatropin). Other side chains than octanoyl were also observed.
[edit] 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>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:. PMID 11162489.</ref><ref>Tschöp M, Smiley DL, Heiman ML (2000). "Ghrelin induces adiposity in rodents". Nature 407 (6806): 908–913. doi:.</ref> by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus<ref>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:. PMID 11069119.</ref><ref>Dickson SL, Leng G, Robinson ICAF. (1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience 54 (2): 303–306. doi:. PMID 8492908.</ref> that include the orexigenic neuropeptide Y (NPY) neurons.<ref>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:. PMID 9003014.</ref> Ghrelin-responsiveness of these neurones is both leptin- and insulin-sensitive.<ref>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:.</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>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:. PMID 16759336.</ref><ref>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: 6–16. doi:. PMID 17407492.</ref> <ref>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:. PMID 12453894.</ref>
[edit] Roles of Ghrelin
- Lung Development
- In the fetuses, it seems that ghrelin is early produced by the lung and promotes its growth.<ref>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): 531–7. doi:. PMID 16549524.</ref>
- Learning and Memory
- Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, enhancing learning and memory.<ref>Learning and memory stimulated by gut hormone | Science Blog</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 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.<ref>Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM (June 15 2008). "The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress". J Nat Neurosci. 11: 752. doi:. PMID 18552842.</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>Newswise: Hunger Hormone Increases During Stress, May Have Antidepressant Effect Retrieved on June 18, 2008.</ref>
- Sleep-Duration
- A study <ref>http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0010062</ref> appearing in the journal PLoS Medicine suggests short sleep durations is associated with high levels of ghrelin and obesity; scientists suggest a factor contributing to the short sleep duration and obesity correlation is ghrelin. Scientists have correlated 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.
[edit] Role in Disease
Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals[1] 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[2]. 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.<ref>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 U S A 101 (28): 10434–9. doi:. 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, among its many other effects, suppresses appetite.
Ghrelin levels are also high in patients that have cancer-induced cachexia.<ref>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:. PMID 15713718.</ref>
Prader-Willi syndrome is also characterized by high fasting levels of ghrelin; here the ghrelin levels are associated with high food intake.<ref>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:. PMID 15070936.</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 that lost weight through dieting alone.<ref>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:. PMID 12023994.</ref>
[edit] 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.<ref>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:. PMID 16284174.</ref> The purpose of this mechanism is unknown.
[edit] History and name
The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999.<ref>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:. 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. 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.
[edit] Anti-obesity vaccine
Recently, Scripps research scientists have developed an anti-obesity vaccine, which is directed against the hormone ghrelin.<ref>Scripps.edu - 'Scripps Research Scientists Successfully Test New Anti-Obesity Vaccine' at The Scripps Research Institute</ref><ref name="pmid16891413">Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, Meijler MM, Janda KD (August 2006). "Vaccination against weight gain". Proc. Natl. Acad. Sci. U.S.A. 103 (35): 13226–31. doi:. PMID 16891413.</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.
[edit] References
[edit] External links
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- 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)
[edit] Source Organism
Canis familiaris (Dog).
[edit] Taxomomy
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae;Canis.
[edit] Subcellular Localization
Secreted protein.
[edit] Developmental Stage
[edit] Similarity
Belongs to the motilin family.
[edit] Post translational Modification
O-n-octanoylation is essential for ghrelin activity (By similarity). Amidation of Leu-98 is essential for obestatin activity (By similarity).
[edit] Function
Ghrelin is the ligand for growth hormone secretagogue receptor type 1 (GHSR). Induces the release of growth hormone from the pituitary. Has an appetite-stimulating effect, induces adiposity and stimulates gastric acid secretion. Involved in growth regulation
[edit] GeneID
403587
