Ghrelin

Ghrelin (Template:IPAc-en; or lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach,<ref name="Kojima1999">Template:Cite journal</ref><ref name="muller">Template:Cite journal</ref> and is often called a "hunger hormone" because it increases the drive to eat.<ref name="muller" /> Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes.<ref name="muller" /><ref>Template:Cite journal</ref> Ghrelin may help prepare for food intake<ref name="muller" /><ref name = "Schwartz_2000"/> by increasing gastric motility and stimulating the secretion of gastric acid.<ref name="muller" />

Ghrelin activates cells in the anterior pituitary gland and hypothalamic arcuate nucleus,<ref name="muller" /><ref name="Dickson1993">Template:Cite journal</ref> including neuropeptide Y neurons that initiate appetite.<ref name="muller" /><ref name="pmid9003014">Template:Cite journal</ref> Ghrelin stimulates brain structures having a specific receptor – the growth hormone secretagogue receptor 1A (GHSR-1A).<ref name="muller" /><ref name="Howard1996">Template:Cite journal</ref> Ghrelin also participates in regulation of reward cognition,<ref name="NHM-Ghrelin">Template:Cite book</ref> learning and memory, the sleep-wake cycle, taste sensation, reward behavior, and glucose metabolism.<ref name="muller" /><ref name="Cholinergic-dopaminergic reward link">Template:Cite journal</ref><ref name="Mesocorticolimbic projection">Template:Cite book</ref>

History and name

Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHS-R) was determined in 1999.<ref name=muller/> 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".<ref name=muller/>

Gene, transcription products, and structure

File:Preproghrelin 1P7X.png

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.<ref name = "pmid19566830">Template:Cite journal</ref>

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.<ref name = "pmid19896496"/> The non-octanoylated form is desacyl ghrelin. It does not activate the GHS-R receptor but does have other effects: cardiac,<ref>Template:Cite journal</ref> anti-ghrelin,<ref>Template:Cite journal</ref> appetite stimulation,<ref>Template:Cite journal</ref> and inhibition of hepatic glucose output.<ref>Template:Cite journal</ref> Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor.<ref>Template:Cite journal</ref> 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.<ref name = "Stengel_Tache_2011" >Template:Cite journal</ref>

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).<ref name="pmid16322794">Template:Cite journal</ref>

Location

Ghrelin cells are found mainly in the stomach<ref name = "pmid11600536">Template:Cite journal</ref> and duodenum, but also in the jejunum, lungs, pancreatic islets,<ref name="pmid18508724">Template:Cite journal</ref> gonads, adrenal cortex, placenta, and kidney. It has also been shown that ghrelin is produced locally in the brain.<ref>Template:Cite journal</ref> Additionally, research suggests that ghrelin may be produced in the myocardium and have an 'autocrine/ paracrine' like effect within the heart.<ref name="Ghrelin and cardiovascular diseases">Template:Cite journal</ref>

Ghrelin cells are also found in oxyntic glands (20% of cells),<ref name="pmid2470131">Template:Cite journal</ref> pyloric glands, and small intestine.

Features

They are ovoid cells with granules.<ref name="pmid94030">Template:Cite journal</ref> They have gastrin receptors.<ref name="pmid18611393">Template:Cite journal</ref> Some produce nesfatin-1.<ref name="pmid19961888">Template:Cite journal</ref> 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.<ref name="pmid23251675">Template:Cite journal</ref>

Function and mechanism of actionTemplate:Anchor

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,<ref name="pmid24732927">Template:Cite book</ref> and both afferent and efferent vagal signals.

Ghrelin and synthetic ghrelin mimetics (growth hormone secretagogues) increase body weight and fat mass<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid27095593">Template:Cite journal</ref> by triggering receptors in the arcuate nucleus<ref name="Dickson1993" /> that include neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons.<ref name="pmid14962995">Template:Cite journal</ref><ref name="pmid9003014" /> Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive.<ref name = "pmid12453894">Template:Cite journal</ref> Ghrelin reduces the sensitivity of gastric vagal afferents, so they are less sensitive to gastric distension.<ref name = "pmid17290011" />

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,<ref name="pmid16137788">Template:Cite journal</ref> a circuit that communicates the hedonic and reinforcing aspects of natural rewards,<ref name="Cholinergic-dopaminergic reward link"/> such as food and addictive drugs such as ethanol.<ref name = "pmid12453894" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Ghrelin receptors are located on neurons in this circuit.<ref name="Cholinergic-dopaminergic reward link" /><ref name="NHM-Ghrelin"/> Hypothalamic ghrelin signalling is required for reward from alcohol<ref name = "pmid19564604">Template:Cite journal</ref> and palatable/rewarding foods.<ref name = "pmid20477752">Template:Cite journal</ref><ref name = "pmid21309956">Template:Cite journal</ref>

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.<ref name = "pmid11897692">Template:Cite journal</ref><ref name = "pmid15039149">Template:Cite journal</ref> Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner.<ref name = "pmid11089570">Template:Cite journal</ref> So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number.<ref name = "pmid12941764">Template:Cite journal</ref> 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.<ref name = "Schwartz_2000">Template:Cite journal</ref>

Blood levels

Blood levels are in the pmol/L or fmol/mL range. Both active and total ghrelin can be measured.<ref name="pmid15863960">Template:Cite journal</ref> Circulating ghrelin concentrations rise before eating and fall afterward,<ref name = "pmid11897692"/> more strongly in response to protein and carbohydrate than to lipids.<ref name = "Stengel_Tache_2011" /> 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.<ref>Template:Cite journal</ref>

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.<ref name="pmid24651458">Template:Cite journal</ref> 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.<ref name = "pmid19896496">Template:Cite journal</ref><ref name = "pmid17290011">Template:Cite journal</ref>

Locations of action

Glucose metabolism

The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a gluco-regulatory action.<ref name="pmid24714083">Template:Cite journal</ref>

Sleep

Preliminary research indicates that ghrelin participates in the regulation of circadian rhythms.<ref name=muller/> A review reported finding strong evidence that sleep restriction affected ghrelin or leptin levels, or energy expenditure.<ref>Template:Cite journal</ref>

Reproductive system

Ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion. It may cause decreased fertility.<ref name = "pmid24173881">Template:Cite journal</ref>

Fetus and neonate

Ghrelin is produced early by the fetal lung and promotes lung growth.<ref>Template:Cite journal</ref> Umbilical cord blood levels of ghrelin show a correlation between ghrelin levels and birth weight.<ref name="pmid15863960"/>

Cardiovascular system

Ghrelin functions as a cardio-protective peptide by being an anti-inflammatory agent, promoting angiogenesis, inhibiting arrhythmia, and improving heart failure.<ref name=":0"/>

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. <ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name="muller2">Template:Cite journal</ref><ref name="pmid120239942">Template:Cite journal</ref> Studies have not clarified whether ghrelin levels return to normal in people who had gastric bypass surgery after weight loss has stabilized.<ref name="pmid128431322">Template:Cite journal</ref> Gastric bypass surgery involving vertical-sleeve gastrectomy reduces plasma ghrelin levels by about 60% in the long term.<ref name="pmid200948192">Template:Cite journal</ref>

Anorexia and obesity

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals,<ref name="muller2" /><ref name="pmid117886532">Template:Cite journal</ref> 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.<ref name="pmid150709362">Template:Cite journal</ref><ref name="pmid124663372">Template:Cite journal</ref> Those with anorexia nervosa have high plasma levels of ghrelin<ref name="pmid247316642">Template:Cite journal</ref> compared to both the constitutionally thin and normal-weight controls.<ref name="pmid125198382">Template:Cite journal</ref><ref name="pmid174130942">Template:Cite journal</ref> 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.<ref name="pmid152319972">Template:Cite journal</ref> Ghrelin levels are high in people with cancer-induced cachexia.<ref name="pmid157137182">Template:Cite journal</ref> There is insufficient evidence to conclude either for or against use of ghrelin in managing cachexia associated with cancer.<ref>Template:Cite journal</ref>

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.<ref name=":0">Template:Cite journal</ref> with exogenous ghrelin being shown to improve heart function in rodent models of chronic heart failure <ref name=":0" /> and improved ventricular remodeling in post-MI rats.<ref name="Ghrelin and cardiovascular diseases"/>

See also

• Hypothalamic–pituitary–somatic axis
• List of growth hormone secretagogues
• Leptin
• Raptin

External links

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