Ghrelin (; or lenomorelin,

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) is a

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

produced by

enteroendocrine cells Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic ef ...

of the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric

motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...

and stimulating the

secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...

. Ghrelin activates cells in the

anterior pituitary gland A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...

and

hypothalamic The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus i ...

arcuate nucleus The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...

, including

neuropeptide Y Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s that initiate

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regu ...

. Ghrelin stimulates brain structures having a specific

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

– the

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

secretagogue receptor 1A ( GHSR-1A). Ghrelin also participates in regulation of reward

cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

, learning and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...

, the sleep-wake cycle,

taste The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste (flavor). Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor ...

sensation, reward behavior, and

glucose metabolism Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms. Carbohydrates are central to many essential metabolic pathways. Plants ...

History and name

Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHS-R) was determined in 1999. The hormone name is based on its role as a ''growth hormone-releasing peptide'', with reference to the

Proto-Indo-European Proto-Indo-European (PIE) is the reconstructed common ancestor of the Indo-European language family. Its proposed features have been derived by linguistic reconstruction from documented Indo-European languages. No direct record of Proto-Indo-E ...

root '' gʰre-'', meaning "to grow".

Gene, transcription products, and structure

The ''GHRL'' gene produces

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

which has four

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s. 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. Ghrelin only becomes active when caprylic (octanoic) acid is linked posttranslationally to

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

at the 3-position by the enzyme

ghrelin O-acyltransferase Ghrelin O-acyltransferase also known as membrane bound O-acyltransferase domain containing 4 is an enzyme that in humans is encoded by the MBOAT4 gene. It is homologous to other membrane-bound O-acyltransferases. It is a polytopic membrane protei ...

(GOAT) to form a proteolipid. It is located on the cell membrane of ghrelin cells in the stomach and

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...

. The non-octanoylated form is desacyl ghrelin. It does not activate the GHS-R receptor but does have other effects: cardiac, anti-ghrelin, appetite stimulation, and inhibition of hepatic glucose output. Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor. 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.

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).

Location

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

Features

Ghrelin cells are found in oxyntic glands (20% of cells), pyloric glands, and small intestine. They are ovoid cells with granules. They have gastrin receptors. Some produce nesfatin-1. 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.

Function and mechanism of action

Ghrelin is a participant in regulating the complex process of

energy homeostasis In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake (energy inflow) and energy expenditure (energy outflow). The human brain, parti ...

which adjusts both ''energy input'' – by adjusting hunger signals – and ''energy output'' – by adjusting the proportion of energy going to

ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...

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 The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...

S6K1 Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of PIP3 ...

pathway mediating the interaction among ghrelin, nesfatin and endocannabinoid gastric systems, and both afferent and efferent vagal signals. Ghrelin and synthetic ghrelin mimetics (

growth hormone secretagogue Growth hormone secretagogues or GH secretagogues (GHSs) are a class of drugs which act as secretagogues (i.e., induce the secretion) of growth hormone (GH). They include agonists of the ghrelin/growth hormone secretagogue receptor (GHSR), such ...

s) increase body weight and fat mass by triggering receptors in the

that include

(NPY) and

agouti-related protein Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nu ...

(AgRP) neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin reduces the sensitivity of gastric

vagal The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right v ...

afferents, so they are less sensitive to gastric distension. In addition to its function in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic reward link in inputs to the

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...

and in the

mesolimbic pathway The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral ...

, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food and addictive drugs such as ethanol. Ghrelin receptors are located on neurons in this circuit. Hypothalamic ghrelin signalling is required for reward from alcohol and palatable/rewarding foods. 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. Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner. So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number. 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 Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular en ...

signal, a messenger between the body's energy stores and the brain.

Blood levels

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

Ghrelin receptor

The ghrelin receptor ''GHS-R1a'' (a splice-variant of the

growth hormone secretagogue receptor Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a G protein-coupled receptor that binds growth hormone secretagogues (GHSs), such as ghrelin, the "hunger hormone". The role of GHS-R is thought to be in regulating en ...

, 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. 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.

Locations of action

Glucose metabolism

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

Sleep

Preliminary research indicates that ghrelin participates in the regulation of

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...

s. A review reported finding strong evidence that sleep restriction affected ghrelin or leptin levels, or energy expenditure.

Reproductive system

Ghrelin has inhibitory effects on

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...

(GnRH) secretion. It may cause decreased fertility.

Fetus and neonate

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

Anorexia and obesity

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals, suggesting that ghrelin does not contribute to obesity, except in the cases of

Prader–Willi syndrome Prader–Willi syndrome (PWS) is a genetic disorder caused by a loss of function of specific genes on chromosome 15. In newborns, symptoms include weak muscles, poor feeding, and slow development. Beginning in childhood, those affected become c ...

-induced obesity, where high ghrelin levels are correlated with increased food intake. Those with

anorexia nervosa Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gr ...

have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls. 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 A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

rhythm of obese individuals. Ghrelin levels are high in people with

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

-induced

cachexia Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart f ...

. There is insufficient evidence to conclude either for or against use of ghrelin in managing cachexia associated with cancer.

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. Studies have not clarified whether ghrelin levels return to normal in people who had gastric bypass surgery after weight loss has stabilized. Gastric bypass surgery involving

vertical-sleeve gastrectomy Sleeve gastrectomy is a surgical weight-loss procedure in which the stomach is reduced to about 15% of its original size, by surgical removal of a large portion of the stomach along the greater curvature. The result is a sleeve or tube like struc ...

reduces plasma ghrelin levels by about 60% in the long term.

References

External links

* * {{GH/IGF-1 axis signaling modulators Appetite stimulants Ghrelin receptor agonists Growth hormone secretagogues Hormones of the somatotropic axis Neuropeptides Obesity Peptide hormones World Anti-Doping Agency prohibited substances