Ghrelin
Ghrelin (
Ghrelin activates cells in the
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
The GHRL gene produces
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]
Ghrelin cells are also found in
Features
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
Ghrelin and synthetic ghrelin mimetics (growth hormone secretagogues) increase body weight and fat mass[34][35][36] by triggering receptors in the arcuate nucleus[9] that include neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons.[37][10] 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.
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]
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.[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 it's 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
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]
Possible Cardiovascular Therapeutic Potential
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]
See also
- Hypothalamic–pituitary–somatic axis
- List of growth hormone secretagogues
- Leptin
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000157017 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000064177 – Ensembl, May 2017
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Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link".
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