Ghrelin

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Ghrelin/obestatin preprohormone
Identifiers
Symbol(s) GHRL; MTLRP; ghrelin; obestatin
External IDs OMIM: 605353 MGI: 1930008 HomoloGene: 9487
Orthologs
Human Mouse
Entrez 51738 58991
Ensembl ENSG00000157017 ENSMUSG00000064177
Uniprot Q9UBU3 Q9EQX0
Refseq NM_016362 (mRNA)
NP_057446 (protein)		 NM_021488 (mRNA)
NP_067463 (protein)
Location 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 appetite.[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. Ghrelin is also produced in the hypothalamic arcuate nucleus where it stimulates the secretion of growth hormone from the anterior pituitary gland.[2] In some 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.[3] 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[4][5] by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus[6][7] that include the orexigenic neuropeptide Y (NPY) neurones[8]. Ghrelin-responsiveness of these neurones is both leptin and insulin sensitive[9]. 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.[10][11] [12]

Role in disease

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals[3] 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[4]. 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.[13] 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.[14]

Ghrelin levels are also high in patients who have cancer-induced cachexia.[15]

Prader-Willi syndrome is also characterized by high fasting levels of ghrelin; here the ghrelin levels are associated with high food intake.[16]

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.[17]

Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, enhancing learning and memory.[18] 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.[19] The purpose of this mechanism is unknown.

History and name

The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999.[20] 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.

Anti-obesity vaccine

Recently Scripps research scientists have developed an anti-obesity vaccine, which is directed against the hormone ghrelin.[21] [22]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.[23] 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.[24]

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. 
  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: 55–59. doi:10.1016/j.regpep.2004.08.038. 
  3. ^ Hunger hormone tied to learning. Retrieved on 2007-06-01. at The Scientist
  4. ^ 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. 
  5. ^ Tschöp M, Smiley DL, Heiman ML (2000). "Ghrelin induces adiposity in rodents". Nature 407 (6806): 908–913. doi:10.1038/35038090. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. year=2002. doi:10.2337/diabetes.51.12.3412. PMID 12453894. 
  10. ^ 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. 
  11. ^ 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:10.1111/j.1369-1600.2006.00041.x. PMID 17407492. 
  12. ^ 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. 
  13. ^ 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:10.1073/pnas.0403465101. PMID 15231997. 
  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): 531–7. doi:10.1203/01.pdr.0000202748.66359.a9. PMID 16549524. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ Learning and memory stimulated by gut hormone | Science Blog
  19. ^ 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. 
  20. ^ 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. 
  21. ^ Scripps.edu - 'Scripps Research Scientists Successfully Test New Anti-Obesity Vaccine' at The Scripps Research Institute
  22. ^ From the Cover: Vaccination against weight gain - Zorrilla et al. 103 (35): 13226 - Proceedings of the National Academy of Sciences
  23. ^ 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). "The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress". J Nat Neurosci. 11: 752. doi:10.1038/nn.2139. PMID 18552842. 
  24. ^ Newswise: Hunger Hormone Increases During Stress, May Have Antidepressant Effect Retrieved on June 18, 2008.

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