Ghrelin

GHRL
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGHRL, MTLRP, ghrelin and obestatin prepropeptide
External IDsOMIM: 605353 MGI: 1930008 HomoloGene: 9487 GeneCards: GHRL
Gene location (Human)
Chromosome 3 (human)
Chr.Chromosome 3 (human)[1]
Chromosome 3 (human)
Genomic location for GHRL
Genomic location for GHRL
Band3p25.3Start10,285,675 bp[1]
End10,292,947 bp[1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_021488
NM_001286404
NM_001286405
NM_001286406

RefSeq (protein)

NP_001273333
NP_001273334
NP_001273335
NP_067463

Location (UCSC)Chr 3: 10.29 – 10.29 MbChr 6: 113.72 – 113.72 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Ghrelin (pronounced /ˈɡrɛlɪn/), is a circulating hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach,[5][6] and is often called a "hunger hormone" because it increases food intake.[6] Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes.[6][7] Ghrelin may help prepare for food intake[6][8] by increasing gastric motility and gastric acid secretion.[6]

Ghrelin activates cells in the anterior pituitary gland and hypothalamic arcuate nucleus,[6][9] including neuropeptide Y neurons that initiate appetite.[6][10] Ghrelin stimulates brain structures having a specific receptor – the growth hormone secretagogue receptor 1A (GHSR-1A).[6][11] Ghrelin also participates in regulation of reward cognition,[12] learning and memory, the sleep-wake cycle, taste sensation, reward behavior, and glucose metabolism.[6][13][14]

History and name

Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHS-R) was determined in 1999.[6] The hormone name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root gʰre-, meaning "to grow".[6]

Gene, transcription products, and structure

Preproghrelin (green and blue) and ghrelin (green).

The GHRL gene produces mRNA which has four exons. Five products arise: the first is the 117-amino acid preproghrelin. (It is homologous to promotilin; both are members of the motilin family). It is cleaved to produce proghrelin which is cleaved to produce a 28-amino acid ghrelin (unacylated) and C-ghrelin(acylated). Obestatin is presumed to be cleaved from C-ghrelin.[15]

Ghrelin only becomes active when caprylic (octanoic) acid is linked posttranslationally to serine at the 3-position by the enzyme ghrelin O-acyltransferase (GOAT). It is located on the cell membrane of ghrelin cells in the stomach and pancreas.[16] The non-octanoylated form is desacyl ghrelin. It does not activate the GHS-R receptor but does have other effects: cardiac,[17] anti-ghrelin,[18] appetite stimulation,[19] and inhibition of hepatic glucose output.[20] Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor.[21] In particular, decanoyl ghrelin has been found to constitute a significant portion of circulating ghrelin in mice, but as of 2011 its presence in humans has not been established.[22]

Ghrelin cells

Alternative names

The ghrelin cell is also known as an A-like cell (pancreas), X-cell (for unknown function), X/A-like cell (rats), Epsilon cell (pancreas), P/D sub 1 cell (humans) and Gr cell (abbreviation for ghrelin cell).[23]

Location

Ghrelin cells are found mainly in the stomach[24] and duodenum, but also in the jejunum, lungs, pancreatic islets,[25] gonads, adrenal cortex, placenta, and kidney. It has recently been shown that ghrelin is produced locally in the brain[26]

Features

Ghrelin cells are found in oxyntic glands (20% of cells),[27] pyloric glands, and small intestine. They are ovoid cells with granules.[28] They have gastrin receptors.[29] Some produce nesfatin-1.[30] Ghrelin cells are not terminally differentiated in the pancreas: they are progenitor cells that can give rise to A-cells, PP cells and Beta-cells there.[31]

Function and mechanism of action

Ghrelin is a participant in regulating the complex process of energy homeostasis which adjusts both energy input – by adjusting hunger signals – and energy output – by adjusting the proportion of energy going to ATP production, fat storage, glycogen storage, and short-term heat loss. The net result of these processes is reflected in body weight, and is under continuous monitoring and adjustment based on metabolic signals and needs. At any given moment in time, it may be in equilibrium or disequilibrium. Gastric-brain communication is an essential part of energy homeostasis, and several communication pathways are probable, including the gastric intracellular mTOR/S6K1 pathway mediating the interaction among ghrelin, nesfatin and endocannabinoid gastric systems,[32] and both afferent and efferent vagal signals.

Ghrelin and synthetic ghrelin mimetics (growth hormone secretagogues) increase body weight and fat mass[33][34][35] by triggering receptors in the arcuate nucleus[9] that include neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons.[36][37] Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive.[38] Ghrelin reduces the sensitivity of gastric vagal afferents, so they are less sensitive to gastric distension.[39]

In addition to its function in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic reward link in inputs to the ventral tegmental area and in the mesolimbic pathway,[40] a circuit that communicates the hedonic and reinforcing aspects of natural rewards,[13] such as food and addictive drugs such as ethanol.[38][41][42] Ghrelin receptors are located on neurons in this circuit.[13][12] Hypothalamic ghrelin signalling is required for reward from alcohol[43] and palatable/rewarding foods.[44][45]

Ghrelin has been linked to inducing appetite and feeding behaviors. Circulating ghrelin levels are the highest right before a meal and the lowest right after.[46][47] Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner.[48] So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number.[49] Ghrelin injections also increase an animal's motivation to seek out food, behaviors including increased sniffing, foraging for food, and hoarding food. Body weight is regulated through energy balance, the amount of energy taken in versus the amount of energy expended over an extended period of time. Studies have shown that ghrelin levels are negatively correlated with weight. This data suggests that ghrelin functions as an adiposity signal, a messenger between the body's energy stores and the brain.[50]

Blood levels

Blood levels are in the pmol/l range. Both active and total ghrelin can be measured.[51] Circulating ghrelin concentrations rise before eating and fall afterward,[46] more strongly in response to protein and carbohydrate than to lipids.[22]

Ghrelin receptor

The ghrelin receptor GHS-R1a (a splice-variant of the growth hormone secretagogue receptor, with the GHS-R1b splice being inactive) is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of growth hormone release, increase in hunger, modulation of glucose and lipid metabolism, regulation of gastrointestinal motility and secretion, protection of neuronal and cardiovascular cells, and regulation of immune function.[52] They are present in high density in the hypothalamus and pituitary, on the vagus nerve (on both afferent cell bodies and efferent nerve endings) and throughout the gastrointestinal tract.[16][39]

Locations of action

Glucose metabolism

The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a gluco-regulatory action.[53]

Sleep

Preliminary research indicates that ghrelin participates in the regulation of circadian rhythms.[6] A review reported finding no strong evidence that sleep restriction affected ghrelin or leptin levels, or energy expenditure.[54]

Reproductive system

Ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion. It may cause decreased fertility.[55]

Fetus and neonate

Ghrelin is produced early by the fetal lung and promotes lung growth.[56] Umbilical cord blood levels of ghrelin show a correlation between ghrelin levels and birth weight.[51]

Anorexia and obesity

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals,[6][57] suggesting that ghrelin does not contribute to obesity, except in the cases of Prader-Willi syndrome-induced obesity, where high ghrelin levels are correlated with increased food intake.[58][59] Those with anorexia nervosa have high plasma levels of ghrelin[60] compared to both the constitutionally thin and normal-weight controls.[61][62] The level of ghrelin increases during the time of day from midnight to dawn in thinner people, which suggests there is a flaw in the circadian rhythm of obese individuals.[63] Ghrelin levels are high in people with cancer-induced cachexia.[64]

Disease management

Gastric bypass surgery

Gastric bypass surgery not only reduces gut capacity for food, but also lowers ghrelin levels compared to both lean people and those who lost weight through dieting.[6][65] Studies have not clarified whether ghrelin levels return to normal in people who had gastric bypass surgery after weight loss has stabilized.[66] Gastric bypass surgery involving vertical-sleeve gastrectomy reduces plasma ghrelin levels by about 60% in the long term.[67]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000157017 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000064177 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Kojima, M; Hosoda, H; Date, Y; Nakazato, M; Matsuo, H; Kangawa, K (9 December 1999). "Ghrelin is a growth-hormone-releasing acylated peptide from stomach". Nature. 402 (6762): 656–60. doi:10.1038/45230. PMID 10604470.
  6. ^ a b c d e f g h i j k l m n Müller, T.D.; Nogueiras, R.; Andermann, M.L.; Andrews, Z.B.; Anker, S.D.; Argente, J.; Batterham, R.L.; Benoit, S.C.; Bowers, C.Y.; Broglio, F.; Casanueva, F.F.; D'Alessio, D.; Depoortere, I.; Geliebter, A.; Ghigo, E.; Cole, P.A.; Cowley, M.; Cummings, D.E.; Dagher, A.; Diano, S.; Dickson, S.L.; Diéguez, C.; Granata, R.; Grill, H.J.; Grove, K.; Habegger, K.M.; Heppner, K.; Heiman, M.L.; Holsen, L.; Holst, B.; Inui, A.; Jansson, J.O.; Kirchner, H.; Korbonits, M.; Laferrère, B.; LeRoux, C.W.; Lopez, M.; Morin, S.; Nakazato, M.; Nass, R.; Perez-Tilve, D.; Pfluger, P.T.; Schwartz, T.W.; Seeley, R.J.; Sleeman, M.; Sun, Y.; Sussel, L.; Tong, J.; Thorner, M.O.; van der Lely, A.J.; van der Ploeg, L.H.T.; Zigman, J.M.; Kojima, M.; Kangawa, K.; Smith, R.G.; Horvath, T.; Tschöp, M.H. (2015). "Ghrelin". Molecular Metabolism. 4 (6): 437–460. doi:10.1016/j.molmet.2015.03.005. ISSN 2212-8778. PMC 4443295. PMID 26042199.
  7. ^ Cummings, DE; Purnell, JQ; Frayo, RS; Schmidova, K; Wisse, BE; Weigle, DS (August 2001). "A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans". Diabetes. 50 (8): 1714–9. doi:10.2337/diabetes.50.8.1714. PMID 11473029.
  8. ^ Schwartz, MW; Woods, SC; Porte D, Jr; Seeley, RJ; Baskin, DG (6 April 2000). "Central nervous system control of food intake". Nature. 404 (6778): 661–71. doi:10.1038/35007534. PMID 10766253.
  9. ^ a b Dickson, SL; Leng, G; Robinson, IC (March 1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience. 53 (2): 303–6. doi:10.1016/0306-4522(93)90197-n. PMID 8492908.
  10. ^ Dickson, SL; Luckman, SM (February 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): 771–7. doi:10.1210/endo.138.2.4907. PMID 9003014.
  11. ^ Howard, AD; Feighner, SD; Cully, DF; Arena, JP; Liberator, PA; Rosenblum, CI; Hamelin, M; Hreniuk, DL; Palyha, OC; Anderson, J; Paress, PS; Diaz, C; Chou, M; Liu, KK; McKee, KK; Pong, SS; Chaung, LY; Elbrecht, A; Dashkevicz, M; Heavens, R; Rigby, M; Sirinathsinghji, DJ; Dean, DC; Melillo, DG; Patchett, AA; Nargund, R; Griffin, PR; DeMartino, JA; Gupta, SK; Schaeffer, JM; Smith, RG; Van der Ploeg, LH (16 August 1996). "A receptor in pituitary and hypothalamus that functions in growth hormone release". Science. 273 (5277): 974–7. doi:10.1126/science.273.5277.974. PMID 8688086.
  12. ^ a b Nestler EJ, Hyman SE, Holtzman DM, Malenka RC (2015). "Neural and Neuroendocrine Control of the Internal Milieu". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. pp. 245–267. ISBN 9780071827690.
  13. ^ Le Moal M (2002). "Mesocorticolimbic Dopaminergic Neurons". In Davis KL, Charney D, Coyle JT, Nemeroff C (eds.). Neuropsychopharmacology : the fifth generation of progress : an official publication of the American College of Neuropsychopharmacology (5th ed.). Philadelphia, Pa.: Lippincott Williams & Wilkins. ISBN 978-0781728379.
  14. ^ Seim I, Amorim L, Walpole C, Carter S, Chopin LK, Herington AC (January 2010). "Ghrelin gene-related peptides: multifunctional endocrine / autocrine modulators in health and disease". Clinical and Experimental Pharmacology & Physiology. 37 (1): 125–31. doi:10.1111/j.1440-1681.2009.05241.x. PMID 19566830.
  15. ^ a b Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH (January 2010). "Ghrelin in the regulation of body weight and metabolism". Frontiers in Neuroendocrinology. 31 (1): 44–60. doi:10.1016/j.yfrne.2009.10.008. PMID 19896496.
  16. ^ Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghé C, Deghenghi R, Ghigo E, Muccioli G (August 2003). "Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin" (PDF). European Journal of Pharmacology. 476 (1–2): 87–95. doi:10.1016/S0014-2999(03)02083-1. hdl:2318/125949. PMID 12969753.
  17. ^ Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, Van Der Lely AJ, Ghigo E (June 2004). "Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans". The Journal of Clinical Endocrinology and Metabolism. 89 (6): 3062–65. doi:10.1210/jc.2003-031964. PMID 15181099.
  18. ^ Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Murakami N, Miyazato M, Kangawa K, Nakazato M (May 2006). "Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor". Endocrinology. 147 (5): 2306–14. doi:10.1210/en.2005-1357. PMID 16484324.
  19. ^ Gauna C, Delhanty PJ, Hofland LJ, Janssen JA, Broglio F, Ross RJ, Ghigo E, van der Lely AJ (February 2005). "Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes". The Journal of Clinical Endocrinology and Metabolism. 90 (2): 1055–56. doi:10.1210/jc.2004-1069. PMID 15536157.
  20. ^ Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB (April 2004). "Ghrelin – a hormone with multiple functions". Frontiers in Neuroendocrinology. 25 (1): 27–68. doi:10.1016/j.yfrne.2004.03.002. PMID 15183037.
  21. ^ a b Stengel A, Taché Y (June 2011). "Interaction between gastric and upper small intestinal hormones in the regulation of hunger and satiety: ghrelin and cholecystokinin take the central stage". Current Protein & Peptide Science. 12 (4): 293–304. doi:10.2174/138920311795906673. PMC 3670092. PMID 21428875.
  22. ^ Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Williams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK (December 2005). "Mice lacking ghrelin receptors resist the development of diet-induced obesity". The Journal of Clinical Investigation. 115 (12): 3564–72. doi:10.1172/JCI26002. PMC 1297251. PMID 16322794.
  23. ^ Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K (October 2001). "Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans". The Journal of Clinical Endocrinology and Metabolism. 86 (10): 4753–58. doi:10.1210/jcem.86.10.7885. PMID 11600536.
  24. ^ Suckale J, Solimena M (2008). "Pancreas islets in metabolic signaling—focus on the beta-cell". Frontiers in Bioscience. 13 (13): 7156–71. doi:10.2741/3218. PMID 18508724.
  25. ^ Ferrini F, Salio C, Lossi L, Merighi A (2009). "Ghrelin in Central Neurons". Current Neuropharmacology. 7 (1): 37–49. doi:10.2174/157015909787602779. PMC 2724662. PMID 19721816.
  26. ^ Simonsson M, Eriksson S, Håkanson R, Lind T, Lönroth H, Lundell L, O'Connor DT, Sundler F (November 1988). "Endocrine cells in the human oxyntic mucosa. A histochemical study". Scandinavian Journal of Gastroenterology. 23 (9): 1089–99. doi:10.3109/00365528809090174. PMID 2470131.
  27. ^ Grube D, Forssmann WG (November 1979). "Morphology and function of the entero-endocrine cells". Hormone and Metabolic Research. 11 (11): 589–606. doi:10.1055/s-0028-1092785. PMID 94030.
  28. ^ Fukumoto K, Nakahara K, Katayama T, Miyazatao M, Kangawa K, Murakami N (September 2008). "Synergistic action of gastrin and ghrelin on gastric acid secretion in rats". Biochemical and Biophysical Research Communications. 374 (1): 60–63. doi:10.1016/j.bbrc.2008.06.114. PMID 18611393.
  29. ^ Inhoff T, Stengel A, Peter L, Goebel M, Taché Y, Bannert N, Wiedenmann B, Klapp BF, Mönnikes H, Kobelt P (February 2010). "Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats". Peptides. 31 (2): 257–62. doi:10.1016/j.peptides.2009.11.024. PMC 4043136. PMID 19961888.
  30. ^ Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L (2012). "Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population". PLOS ONE. 7 (12): e52026. Bibcode:2012PLoSO...752026A. doi:10.1371/journal.pone.0052026. PMC 3520898. PMID 23251675.
  31. ^ Folgueira C, Seoane LM, Casanueva FF (2014). "The brain-stomach connection". In Delhanty PJD, van der Lely AJ (eds.). How Gut and Brain Control Metabolism. Frontiers of Hormone Research. 42. Basel: Karger. pp. 83–92. doi:10.1159/000358316. ISBN 978-3-318-02638-2. PMID 24732927.
  32. ^ Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL (January 2001). "Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues". Biochemical and Biophysical Research Communications. 280 (1): 132–38. doi:10.1006/bbrc.2000.4065. PMID 11162489.
  33. ^ Tschöp M, Smiley DL, Heiman ML (October 2000). "Ghrelin induces adiposity in rodents". Nature. 407 (6806): 908–13. Bibcode:2000Natur.407..908T. doi:10.1038/35038090. PMID 11057670.
  34. ^ Chebani Y, Marion C, Zizzari P, Chettab K, Pastor M, Korostelev M, Geny D, Epelbaum J, Tolle V, Morisset-Lopez S, Pantel J (2016). "Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite" (PDF). Science Signaling. 9 (424): ra39. doi:10.1126/scisignal.aae0374. PMID 27095593.
  35. ^ Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, Shen Z, Marsh DJ, Feighner SD, Guan XM, Ye Z, Nargund RP, Smith RG, Van der Ploeg LH, Howard AD, MacNeil DJ, Qian S (2004). "Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein". Endocrinology. 145 (6): 2607–12. doi:10.1210/en.2003-1596. PMID 14962995.
  36. ^ Dickson SL, Luckman SM (February 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): 771–77. doi:10.1210/en.138.2.771. PMID 9003014.
  37. ^ a b Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL (December 2002). "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes. 51 (12): 3412–19. doi:10.2337/diabetes.51.12.3412. PMID 12453894.
  38. ^ a b Page AJ, Slattery JA, Milte C, Laker R, O'Donnell T, Dorian C, Brierley SM, Blackshaw LA (May 2007). "Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents". American Journal of Physiology. Gastrointestinal and Liver Physiology. 292 (5): 1376–84. doi:10.1152/ajpgi.00536.2006. PMID 17290011.
  39. ^ Naleid AM, Grace MK, Cummings DE, Levine AS (2005). "Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens". Peptides. 26 (11): 2274–79. doi:10.1016/j.peptides.2005.04.025. PMID 16137788.
  40. ^ Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA (March 2006). "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.
  41. ^ Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA (March 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.
  42. ^ Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA (July 2009). "Requirement of central ghrelin signaling for alcohol reward". Proceedings of the National Academy of Sciences of the United States of America. 106 (27): 11318–23. Bibcode:2009PNAS..10611318J. doi:10.1073/pnas.0812809106. PMC 2703665. PMID 19564604.
  43. ^ Egecioglu E, Jerlhag E, Salomé N, Skibicka KP, Haage D, Bohlooly-Y M, Andersson D, Bjursell M, Perrissoud D, Engel JA, Dickson SL (July 2010). "Ghrelin increases intake of rewarding food in rodents". Addiction Biology. 15 (3): 304–11. doi:10.1111/j.1369-1600.2010.00216.x. PMC 2901520. PMID 20477752.
  44. ^ Skibicka KP, Hansson C, Egecioglu E, Dickson SL (January 2012). "Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression". Addiction Biology. 17 (1): 95–107. doi:10.1111/j.1369-1600.2010.00294.x. PMC 3298643. PMID 21309956.
  45. ^ a b Tolle V, Bassant MH, Zizzari P, Poindessous-Jazat F, Tomasetto C, Epelbaum J, Bluet-Pajot MT (2002). "Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats". Endocrinology. 143 (4): 1353–61. doi:10.1210/endo.143.4.8712. PMID 11897692.
  46. ^ Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D (August 2004). "Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues". American Journal of Physiology. Endocrinology and Metabolism. 287 (2): E297–304. doi:10.1152/ajpendo.00582.2003. PMID 15039149.
  47. ^ Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR (November 2000). "The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion". Endocrinology. 141 (11): 4325–28. doi:10.1210/endo.141.11.7873. PMID 11089570.
  48. ^ Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ (September 2003). "Hyperphagic effects of brainstem ghrelin administration". Diabetes. 52 (9): 2260–65. doi:10.2337/diabetes.52.9.2260. PMID 12941764.
  49. ^ Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG (April 2000). "Central nervous system control of food intake". Nature. 404 (6778): 661–71. doi:10.1038/35007534. PMID 10766253.
  50. ^ a b Yokota I, Kitamura S, Hosoda H, Kotani Y, Kangawa K (April 2005). "Concentration of the n-octanoylated active form of ghrelin in fetal and neonatal circulation". Endocrine Journal. 52 (2): 271–76. doi:10.1507/endocrj.52.271. PMID 15863960.
  51. ^ Yin Y, Li Y, Zhang W (2014). "The growth hormone secretagogue receptor: its intracellular signaling and regulation". International Journal of Molecular Sciences. 15 (3): 4837–55. doi:10.3390/ijms15034837. PMC 3975427. PMID 24651458.
  52. ^ Heppner KM, Tong J (July 2014). "Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions". European Journal of Endocrinology. 171 (1): R21–32. doi:10.1530/EJE-14-0183. PMID 24714083.
  53. ^ Zhu B, Shi C, Park CG, Zhao X, Reutrakul S (June 2019). "Effects of sleep restriction on metabolism-related parameters in healthy adults: A comprehensive review and meta-analysis of randomized controlled trials". Sleep Med Rev. 45: 18–30. doi:10.1016/j.smrv.2019.02.002. PMID 30870662.
  54. ^ Comninos AN, Jayasena CN, Dhillo WS (2014). "The relationship between gut and adipose hormones, and reproduction". Human Reproduction Update. 20 (2): 153–74. doi:10.1093/humupd/dmt033. PMID 24173881.
  55. ^ Santos M, Bastos P, Gonzaga S, Roriz JM, Baptista MJ, Nogueira-Silva C, Melo-Rocha G, Henriques-Coelho T, Roncon-Albuquerque R, Leite-Moreira AF, De Krijger RR, Tibboel D, Rottier R, Correia-Pinto J (April 2006). "Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia". Pediatric Research. 59 (4 Pt 1): 531–37. doi:10.1203/01.pdr.0000202748.66359.a9. PMID 16549524.
  56. ^ Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S (January 2002). "Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion". The Journal of Clinical Endocrinology and Metabolism. 87 (1): 240–4. doi:10.1210/jcem.87.1.8129. PMID 11788653.
  57. ^ Goldstone AP, Thomas EL, Brynes AE, Castroman G, Edwards R, Ghatei MA, Frost G, Holland AJ, Grossman AB, Korbonits M, Bloom SR, Bell JD (April 2004). "Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance". The Journal of Clinical Endocrinology and Metabolism. 89 (4): 1718–26. doi:10.1210/jc.2003-031118. PMID 15070936.
  58. ^ DelParigi A, Tschöp M, Heiman ML, Salbe AD, Vozarova B, Sell SM, Bunt JC, Tataranni PA (December 2002). "High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader-Willi syndrome". The Journal of Clinical Endocrinology and Metabolism. 87 (12): 5461–4. doi:10.1210/jc.2002-020871. PMID 12466337.
  59. ^ Misra M, Klibanski A (July 2014). "Endocrine consequences of anorexia nervosa". The Lancet Diabetes & Endocrinology. 2 (7): 581–92. doi:10.1016/S2213-8587(13)70180-3. PMC 4133106. PMID 24731664.
  60. ^ Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum J, Estour B (2003). "Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women". The Journal of Clinical Endocrinology and Metabolism. 88 (1): 109–16. doi:10.1210/jc.2002-020645. PMID 12519838.
  61. ^ Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F, Bloom SR, Estour B (April 2007). "Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin". The American Journal of Clinical Nutrition. 85 (4): 967–71. doi:10.1093/ajcn/85.4.967. PMID 17413094.
  62. ^ Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J (July 2004). "Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity". Proceedings of the National Academy of Sciences of the United States of America. 101 (28): 10434–39. Bibcode:2004PNAS..10110434Y. doi:10.1073/pnas.0403465101. PMC 478601. PMID 15231997.
  63. ^ Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, Smith RG, Cunningham GR, Marcelli M (May 2005). "Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia". The Journal of Clinical Endocrinology and Metabolism. 90 (5): 2920–26. doi:10.1210/jc.2004-1788. PMID 15713718.
  64. ^ Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (May 2002). "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery". The New England Journal of Medicine. 346 (21): 1623–30. doi:10.1056/NEJMoa012908. PMID 12023994.
  65. ^ Cummings DE, Shannon MH (July 2003). "Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss?". The Journal of Clinical Endocrinology and Metabolism. 88 (7): 2999–3002. doi:10.1210/jc.2003-030705. PMID 12843132.
  66. ^ Bohdjalian A, Langer FB, Shakeri-Leidenmühler S, Gfrerer L, Ludvik B, Zacherl J, Prager G (May 2010). "Sleeve gastrectomy as sole and definitive bariatric procedure: 5-year results for weight loss and ghrelin". Obesity Surgery. 20 (5): 535–40. doi:10.1007/s11695-009-0066-6. PMID 20094819.