Ghrelin

Ghrelin /ˈɡrɛlɪn/ (or lenomorelin, INN) 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]

GHRL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1P7X,%%s2JSH, 2JSI, 2JSJ
Identifiers
Aliases	GHRL, MTLRP, ghrelin and obestatin prepropeptide, Ghrelin
External IDs	OMIM: 605353 MGI: 1930008 HomoloGene: 9487 GeneCards: GHRL
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p25.3 Start 10,285,666 bp[1] End 10,292,947 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 E3|6 52.84 cM Start 113,716,119 bp[2] End 113,719,880 bp[2]
Gene ontology Molecular function • protein tyrosine kinase activator activity • hormone activity • GO:0001948 protein binding • ghrelin receptor binding • G-protein coupled receptor binding • growth hormone-releasing hormone activity Cellular component • postsynapse • cytoplasm • endoplasmic reticulum lumen • extracellular region • axon • secretory granule lumen • extracellular • Schaffer collateral - CA1 synapse • glutamatergic synapse Biological process • positive regulation of appetite • negative regulation of interleukin-6 biosynthetic process • G-protein coupled receptor signaling pathway • positive regulation of cortisol secretion • positive regulation of growth hormone receptor signaling pathway • negative regulation of insulin secretion • gastric acid secretion • positive regulation of cytosolic calcium ion concentration • dendrite development • regulation of response to food • negative regulation of apoptotic process • positive regulation of corticotropin secretion • negative regulation of locomotion • cortisol secretion • response to estrogen • negative regulation of endothelial cell proliferation • positive regulation of circadian sleep/wake cycle, non-REM sleep • negative regulation of tumor necrosis factor biosynthetic process • cartilage development • activation of MAPK activity • decidualization • regulation of cell proliferation • growth hormone secretion • positive regulation of growth hormone secretion • excitatory postsynaptic potential • hormone-mediated signaling pathway • glucose metabolic process • positive regulation of multicellular organism growth • negative regulation of angiogenesis • response to hormone • actin polymerization or depolymerization • positive regulation of response to food • negative regulation of circadian sleep/wake cycle, REM sleep • negative regulation of inflammatory response • positive regulation of insulin secretion • positive regulation of synapse assembly • positive regulation of protein tyrosine kinase activity • adult feeding behavior • response to nutrient levels • positive regulation of eating behavior • positive regulation of adipose tissue development • negative regulation of interleukin-1 beta production • gastric emptying • positive regulation of insulin secretion involved in cellular response to glucose stimulus • positive regulation of growth • response to electrical stimulus • regulation of transmission of nerve impulse • positive regulation of bone development • positive regulation of sprouting angiogenesis • positive regulation of gastro-intestinal system smooth muscle contraction • positive regulation of small intestine smooth muscle contraction • negative regulation of tumor necrosis factor secretion • regulation of gastric motility • positive regulation of vascular endothelial cell proliferation • positive regulation of growth rate • positive regulation of small intestinal transit • positive regulation of gastric mucosal blood circulation • positive regulation of feeding behavior • regulation of receptor activity • energy homeostasis • postsynaptic modulation of chemical synaptic transmission • regulation of postsynapse organization • positive regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	51738	58991
Ensembl	ENSG00000157017	ENSMUSG00000064177
UniProt	Q9UBU3	Q9EQX0
RefSeq (mRNA)	NM_001134941 NM_001134944 NM_001134945 NM_001134946 NM_001302821 NM_001302822 NM_001302823 NM_001302824 NM_001302825 NM_016362	NM_021488 NM_001286404 NM_001286405 NM_001286406 NM_001379129
RefSeq (protein)	NP_001128413 NP_001128416 NP_001128417 NP_001128418 NP_001289750 NP_001289751 NP_001289752 NP_001289753 NP_001289754 NP_057446 NP_001128413 NP_001128416 NP_001128417 NP_001128418 NP_001289750 NP_001289751 NP_001289752 NP_001289753 NP_001289754 NP_057446	NP_001273333 NP_001273334 NP_001273335 NP_067463 NP_001366058
Location (UCSC)	Chr 3: 10.29 – 10.29 Mb	Chr 6: 113.72 – 113.72 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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 also 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][10] Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive.[37] Ghrelin reduces the sensitivity of gastric vagal afferents, so they are less sensitive to gastric distension.[38]

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,[39] a circuit that communicates the hedonic and reinforcing aspects of natural rewards,[13] such as food and addictive drugs such as ethanol.[37][40][41] Ghrelin receptors are located on neurons in this circuit.[13][12] Hypothalamic ghrelin signalling is required for reward from alcohol[42] and palatable/rewarding foods.[43][44]

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.[45][46] Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner.[47] So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number.[48] 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.[8]

Blood levels

Blood levels are in the pmol/l range. Both active and total ghrelin can be measured.[49] Circulating ghrelin concentrations rise before eating and fall afterward,[45] 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.[50] 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][38]

Locations of action

Glucose metabolism

The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a gluco-regulatory action.[51]

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.[52]

Reproductive system

Ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion. It may cause decreased fertility.[53]

Fetus and neonate

Ghrelin is produced early by the fetal lung and promotes lung growth.[54] Umbilical cord blood levels of ghrelin show a correlation between ghrelin levels and birth weight.[49]

Anorexia and obesity

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals,[6][55] 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.[56][57] Those with anorexia nervosa have high plasma levels of ghrelin[58] compared to both the constitutionally thin and normal-weight controls.[59][60] 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.[61] Ghrelin levels are high in people with cancer-induced cachexia.[62] There is insufficient evidence to conclude either for or against use of ghrelin in managing cachexia associated with cancer.[63]

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][64] Studies have not clarified whether ghrelin levels return to normal in people who had gastric bypass surgery after weight loss has stabilized.[65] Gastric bypass surgery involving vertical-sleeve gastrectomy reduces plasma ghrelin levels by about 60% in the long term.[66]

See also

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

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External links

• Overview of all the structural information available in the PDB for UniProt: Q9UBU3 (Human Appetite-regulating hormone) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q9EQX0 (Mouse Appetite-regulating hormone) at the PDBe-KB.