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Ghrelin

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ghrelin/obestatin preprohormone
Identifiers
SymbolGHRL
NCBI gene51738
HGNC18129
OMIM605353
RefSeqNM_016362
UniProtQ9UBU3
Other data
LocusChr. 3 p26-p25
Search for
StructuresSwiss-model
DomainsInterPro

Ghrelin is a hormone produced by P/D1 cells lining the acer of the human stomach that stimulate appetite.[1] In rodents, X/A-like cells produce ghrelin. 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 also stimulates the secretion of growth hormone from the anterior pituitary gland. 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.[2] Recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.

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[3][4] by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus[5][6] that include the orexigenic neuropeptide Y (NPY) neurones[7]. Ghrelin-responsiveness of these neurones is both leptin and insulin sensitive[8]. 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.[9][10] [11]

Role in disease

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals. 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.[12] 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.[13] 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.[14]

Prader-Willi syndrome is also characterized by high fasting levels of ghrelin; here the ghrelin levels are associated with high food intake.[15]

At least one study found that gastric bypass surgery not only reduces the gut's capacity for food, but also dramatically lowers ghrelin levels.[16]

Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, enhancing learning and memory.[17] 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

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.[18] The purpose of this mechanism is unknown.

History and name

The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999.[19] 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.[20] 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  2. ^ "Hunger hormone tied to learning". Retrieved 2007-06-01. at The Scientist
  3. ^ 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. PMID 11162489.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Tschöp M, Smiley DL, Heiman ML (2000). "Ghrelin induces adiposity in rodents". Nature. 407 (6806): 908–913.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ 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. PMID 11069119.
  6. ^ Dickson SL, Leng G, Robinson ICAF. (1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience. 54 (2): 303–306. PMID 8492908. {{cite journal}}: Text "doi:10.1016/0306-4522(93)90197-N" ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ 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. PMID 9003014.
  8. ^ Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL. "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes. 51 (12): 3412-3419. year=2002. PMID 12453894. {{cite journal}}: Missing pipe in: |pages= (help)CS1 maint: multiple names: authors list (link)
  9. ^ 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. PMID 16759336.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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. PMID 17407492.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ 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. PMID 15231997.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ 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. PMID 16549524.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ 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. PMID 15713718.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ 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. PMID 15070936.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ 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. PMID 12023994.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ http://www.scienceblog.com/cms/learning_and_memory_stimulated_by_gut_hormone_10083.html
  18. ^ 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. PMID 16284174.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ 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. PMID 10604470.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Scripps.edu - 'Scripps Research Scientists Successfully Test New Anti-Obesity Vaccine' at The Scripps Research Institute
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