Ghrelin (/ˈɡrɛlɪn/; or lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach,[5][6] and is often called a "hunger hormone" because it increases the drive to eat.[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 stimulating the secretion of gastric acid.[6]
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 an unacylated 28-amino acid ghrelin and an acylated C-ghrelin. 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) to form a proteolipid. 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 also been shown that ghrelin is produced locally in the brain.[26] Additionally, research suggests that ghrelin may be produced in the myocardium and have an 'autocrine/ paracrine' like effect within the heart.[27]
They are ovoid cells with granules.[29] They have gastrin receptors.[30] Some produce nesfatin-1.[31] 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.[32]
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,[33] and both afferent and efferent vagal signals.
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 positively correlated with weight. This data suggests that ghrelin functions as an adiposity signal, a messenger between the body's energy stores and the brain.[8]
Blood levels
Blood levels are in the pmol/L or fmol/mL range. Both active and total ghrelin can be measured.[50] Circulating ghrelin concentrations rise before eating and fall afterward,[46] more strongly in response to protein and carbohydrate than to lipids.[22] The plasma ghrelin-like immunoreactivity concentration measured with a particular radioimmunoassay in a typical human is 166.0 + 10.1 fmol/mL. Serum ghrelin concentrations tend to increase in age and vary throughout the day, with values peaking while one is asleep.[51]
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 strong evidence that sleep restriction affected ghrelin or leptin levels, or energy expenditure.[54]
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.[50]
Cardiovascular system
Ghrelin functions as a cardio-protective peptide by being an anti-inflammatory agent, promoting angiogenesis, inhibiting arrhythmia, and improving heart failure.[57]
Immune system
Ghrelin has a diverse immunoregulatory role mediating the release of anti-inflammatory cytokines such as IL-4 and 10 along with TGF-β while reducing pro-inflammatory cytokines such as TNF-α, INF-γ, and IL-1β from various immunologically competent cells in vitro and in vivo.[58] Additionally, Ghrelin and its endogenous receptor, GHSR1a, along with GOAT are expressed in primary immune tissues such as the spleen and thymus where it has a role in modulating interactions between metabolic state and inflammation, mediating energy balance homeostasis.[59]
Stress/ Hypothalamic-pituitary-adrenal (HPA) axis
GHSR1A, Ghrelin's endogenous receptor, is expressed within the hypothalamus including the arcuate nucleus, but not in the paraventricular nucleus (PVN) where ghrelin has been found to indirectly affect HPA axis function via neighboring corticotropin releasing hormone (CRH) neurons.[60] Studies regarding how ghrelin affects cortisol and adrenocorticotropic hormone (ACTH) secretion along with how cortisol and ACTH levels affect ghrelin are inconsistent as different psychological and physical stressors within in vivo studies have produced a myriad of results as the underlying mechanisms are still not understood well.[61]
Role(s) in disease
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.[62][63] Studies have not clarified whether ghrelin levels return to normal in people who had gastric bypass surgery after weight loss has stabilized.[64] Gastric bypass surgery involving vertical-sleeve gastrectomy reduces plasma ghrelin levels by about 60% in the long term.[65]
Anorexia and obesity
Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals,[62][66] 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.[67][68] Those with anorexia nervosa have high plasma levels of ghrelin[69] compared to both the constitutionally thin and normal-weight controls.[70][71] 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.[72] Ghrelin levels are high in people with cancer-induced cachexia.[73] There is insufficient evidence to conclude either for or against use of ghrelin in managing cachexia associated with cancer.[74]
Effects on cardiovascular system
Ghrelin has been theorized to have protective effects on the cardiovascular system. Studies have shown that in mice models of myocardial infarction (MI) with knock-outs of ghrelin, subjects with no endogenous ghrelin production had a significantly increased mortality rate along with worse metrics in terms of cardiac sympathetic activity and systolic function when compared to wild-type subjects.[57] with exogenous ghrelin being shown to improve heart function in rodent models of chronic heart failure [57] and improved ventricular remodeling in post-MI rats.[27]
^ abNestler 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. ISBN9780071827690.
^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. ISBN978-0781728379. Archived from the original on 5 February 2018. Retrieved 21 May 2014.
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^Grube D, Forssmann WG (November 1979). "Morphology and function of the entero-endocrine cells". Hormone and Metabolic Research = Hormon- und Stoffwechselforschung = Hormones et Metabolisme. 11 (11): 589–606. doi:10.1055/s-0028-1092785. PMID94030. S2CID40287472.
^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. PMID18611393.
^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. Vol. 42. Basel: Karger. pp. 83–92. doi:10.1159/000358316. ISBN978-3-318-02638-2. PMID24732927.
^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): 132–138. doi:10.1006/bbrc.2000.4065. PMID11162489.
^ abPage AJ, Slattery JA, Milte C, Laker R, O'Donnell T, Dorian C, et al. (May 2007). "Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents". American Journal of Physiology. Gastrointestinal and Liver Physiology. 292 (5): G1376–G1384. doi:10.1152/ajpgi.00536.2006. PMID17290011. S2CID10681559.
^Naleid AM, Grace MK, Cummings DE, Levine AS (November 2005). "Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens". Peptides. 26 (11): 2274–2279. doi:10.1016/j.peptides.2005.04.025. PMID16137788. S2CID25619880.
^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. PMID16759336. S2CID33650732.
^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. PMID17407492. S2CID22556527.
^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–E304. doi:10.1152/ajpendo.00582.2003. PMID15039149. S2CID14197143.
^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 Medicine Reviews. 45: 18–30. doi:10.1016/j.smrv.2019.02.002. PMID30870662. S2CID78091930.
^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): 535–540. doi:10.1007/s11695-009-0066-6. PMID20094819. S2CID207303352.
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