Ghrelin
Encyclopedia
Ghrelin is a 28 amino acid peptide and hormone
that is produced mainly by P/D1 cell
s lining the fundus
of the human stomach
and epsilon cells
of the pancreas
that stimulates hunger
. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin
, produced by adipose tissue
, which induces satiation when present at higher levels. In some bariatric
procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.
Ghrelin is a potent stimulator of growth hormone
from the anterior pituitary gland. The ghrelin receptor is a G protein-coupled receptor
, known as the growth hormone secretagogue receptor
. Ghrelin binds to the GHSR1a splice-variant of this receptor which is present in high density in the hypothalamus, pituitary as well as vagal afferent cell bodies and vagal afferent endings throughout the gastro-intestinal tract
Ghrelin plays a significant role in neurotrophy, particularly in the hippocampus
, and is essential for cognitive adaptation to changing environments and the process of learning
. Recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase
in a pathway that depends on various kinase
s including Akt
.
root ghre, meaning to grow. The name can also be viewed as an interesting (and incidental) pun, too, as the initial letters of the phrase growth hormone-releasing give us "ghre" with "lin" as a usual suffix for some hormones.
'Ghrelin' usually refers to the octanoylated form of ghrelin (acyl ghrelin). This is the 28 amino acid peptide sequence with an octanoylation on the third amino acid (Serine). The octanoylation is performed by the Ghrelin O-acyltransferase (GOAT) protein (a member of the membrane-bound O-Acyltransferase family of proteins), located in the stomach and pancreas. This peptide can activate the GHSR receptor and is thus known as the active form of ghrelin. The non-octanoylated form is known as desacyl ghrelin or the inactive form (it does not activate GHSR1a and thus does not release GH like acyl ghrelin), however studies have shown it has its own effects . Side chains other than octanoyl have also been observed.
that include the orexigenic neuropeptide Y (NPY) neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as ethanol.
There is also strong evidence that ghrelin has a peripheral appetite modulatory effect on satiety by affecting the mechanosensitivity of gastric vagal afferents, making them less sensitive to distension resulting in over eating.
is a putative hormone that was described, in late 2005, to decrease appetite. Both obestatin and ghrelin are encoded by the same gene
; the gene's product breaks apart to yield the two peptide hormones. The physiological value of this mechanism is unknown, and it should be noted that no secretory convertase is capable of cleaving the recombinant precursor by cleavage at the single basic residue required for generation of obestatin; thus the physiological generation of this peptide is questionable.
during inflammatory states and oxidative stress
. It also suppresses the pro-inflammatory mechanisms and augments anti-inflammatory mechanisms thus creating a possibility of its therapeutic use in various gastrointestinal inflammatory conditions including colitis
, ischemia reperfusion injury
and sepsis
. In fact, animal models of colitis, ischemia re-perfusion and sepsis related gut dysfunction have been shown to be benefited with therapeutic doses of ghrelin. It has also been shown to have regenerative capacity and is beneficial in case of mucosal injury to the stomach. Ghrelin also enhances the motility of gastrointestinal tract, as does motilin
. Ghrelin also appears to promote gastrointestinal and pancreatic malignancy.
s indicate that ghrelin may enter the hippocampus
from the blood
stream, altering nerve-cell
connections
, and so enhancing learn
ing and memory
. It is suggested that learning may be best during the day and when the stomach is empty, since ghrelin levels are higher at these times. The team of the Yale School of Medicine
also noted that a similar effect for human neural
-physiology
is quite plausible. In rodents, X/A-like cells produce ghrelin.
and anxiety
. To test whether ghrelin could regulate depressive symptoms brought on by chronic stress
, the researchers subjected mice to daily bouts of social stress, using a standard laboratory technique that induces stress by exposing normal mice to very aggressive “bully” mice. Such animals have been shown to be good models for studying depression in humans. The researchers stressed both wild-type mice and altered mice that were unable to respond to ghrelin. They found that, after experiencing stress, both types of mice had significantly elevated levels of ghrelin that persisted at least four weeks after their last defeat encounter. The altered mice, however, displayed significantly greater social avoidance than their wild-type counterparts, indicating an exacerbation of depression-like symptoms. They also ate less than the wild-type mice.
suggests that short sleep duration is associated with high levels of ghrelin and obesity; ghrelin appears to be a factor contributing to the short sleep duration and obesity. Scientists have uncovered an inverse relationship between the hours of sleep and blood plasma concentrations of ghrelin; as the hours of sleep increase, ghrelin concentrations were considerably lower, thereby potentially reducing appetite and avoiding potential obesity.
individuals are lower than those in leaner individuals thus 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 . Those suffering from the eating disorder anorexia nervosa
have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls.. The use of Ghrelin on Anorexia Nervosa patients has been shown to increase food intake by 12-36% over the trial period.
Yildiz and colleagues found that the level of ghrelin increases during the time of day from midnight to dawn in thinner people, suggesting a flaw in the circadian
system of obese individuals. Professor Cappuccio of the University of Warwick
has recently discovered that short sleep
duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces ghrelin, which stimulates appetite and creates less leptin
, which, among its many other effects, suppresses appetite.
Ghrelin levels are also high in patients that have cancer-induced cachexia
.
At least one study found that gastric bypass surgery not only reduces the gut's capacity for food but also dramatically lowers ghrelin levels compared to both lean controls and those that lost weight through dieting alone.
Ghrelin through its receptor increases the concentration of dopamine
in the substantia nigra
, a region of the brain where dopamine cell degeneration leads to Parkinson's disease
. Hence ghrelin may find application in slowing down the onset of Parkinson's disease.
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
that is produced mainly by P/D1 cell
P/D1 cell
Cells lining the fundus of the human stomach that produce ghrelin. Removal of these cells in gastric bypass surgery has a profound impact on later appetite regulation....
s lining the fundus
Fundus (stomach)
The fundus of the stomach is the left portion of the stomach's body, and is marked off from the remainder of the body by a plane passing horizontally through the cardiac orifice....
of the human stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
and epsilon cells
Epsilon cell
Epsilon cells are endocrine cells found in the Islets of Langerhans and produce the hormone ghrelin. They were recently discovered in mice.- References :http://www.ihop-net.org/UniPub/iHOP/pm/10257219.html?pmid=14970313...
of the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
that stimulates hunger
Hunger
Hunger is the most commonly used term to describe the social condition of people who frequently experience the physical sensation of desiring food.-Malnutrition, famine, starvation:...
. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
, produced by adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
, which induces satiation when present at higher levels. In some bariatric
Bariatrics
Bariatrics is the branch of medicine that deals with the causes, prevention, and treatment of obesity. The term bariatrics was created around 1965, from the Greek root bar- , suffix -iatr , and suffix -ic...
procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.
Ghrelin is a potent stimulator of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
from the anterior pituitary gland. The ghrelin receptor is a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
, known as the growth hormone secretagogue receptor
Growth hormone secretagogue receptor
Growth hormone secretagogue receptor is a G protein-coupled receptor that binds ghrelin and plays a role in energy homeostasis and regulation of body weight.-Function:...
. Ghrelin binds to the GHSR1a splice-variant of this receptor which is present in high density in the hypothalamus, pituitary as well as vagal afferent cell bodies and vagal afferent endings throughout the gastro-intestinal tract
Ghrelin plays a significant role in neurotrophy, particularly in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, and is essential for cognitive adaptation to changing environments and the process of learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
. Recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
in a pathway that depends on various kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s including Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
.
History and name
The discovery of ghrelin followed after the discovery of the ghrelin receptor in 1996 and was reported by Masayasu Kojima and colleagues in 1999. The name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-EuropeanProto-Indo-European language
The Proto-Indo-European language is the reconstructed common ancestor of the Indo-European languages, spoken by the Proto-Indo-Europeans...
root ghre, meaning to grow. The name can also be viewed as an interesting (and incidental) pun, too, as the initial letters of the phrase growth hormone-releasing give us "ghre" with "lin" as a usual suffix for some hormones.
Synthesis and variants
The mRNA from the ghrl gene codes for a 117 amino acid peptide called preproghrelin, containing 4 exons of the GHRL gene. The signalling peptide molecule of this larger precursor is cleaved to produce proghrelin. Proghrelin is cleaved in two to produce the 28 amino acid peptide ghrelin (unacylated) and C-ghrelin (of which obestatin is presumed to be cleaved from) .'Ghrelin' usually refers to the octanoylated form of ghrelin (acyl ghrelin). This is the 28 amino acid peptide sequence with an octanoylation on the third amino acid (Serine). The octanoylation is performed by the Ghrelin O-acyltransferase (GOAT) protein (a member of the membrane-bound O-Acyltransferase family of proteins), located in the stomach and pancreas. This peptide can activate the GHSR receptor and is thus known as the active form of ghrelin. The non-octanoylated form is known as desacyl ghrelin or the inactive form (it does not activate GHSR1a and thus does not release GH like acyl ghrelin), however studies have shown it has its own effects . Side chains other than octanoyl have also been observed.
Mechanism of action
Ghrelin has emerged as the first identified circulating hunger hormone. Ghrelin and synthetic ghrelin mimetics (the growth hormone secretagogues) increase food intake and increase fat mass by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleusArcuate nucleus
The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence...
that include the orexigenic neuropeptide Y (NPY) neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive. Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as ethanol.
There is also strong evidence that ghrelin has a peripheral appetite modulatory effect on satiety by affecting the mechanosensitivity of gastric vagal afferents, making them less sensitive to distension resulting in over eating.
Relation to obestatin
ObestatinObestatin
Obestatin is a putative hormone that is potentially produced in the cells lining the stomach and small intestine of several mammals including humans...
is a putative hormone that was described, in late 2005, to decrease appetite. Both obestatin and ghrelin are encoded by the same gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
; the gene's product breaks apart to yield the two peptide hormones. The physiological value of this mechanism is unknown, and it should be noted that no secretory convertase is capable of cleaving the recombinant precursor by cleavage at the single basic residue required for generation of obestatin; thus the physiological generation of this peptide is questionable.
Gastrointestinal tract
Ghrelin has been proposed as a hormone which promotes intestinal cell proliferation and inhibits its apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
during inflammatory states and oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. It also suppresses the pro-inflammatory mechanisms and augments anti-inflammatory mechanisms thus creating a possibility of its therapeutic use in various gastrointestinal inflammatory conditions including colitis
Colitis
In medicine, colitis refers to an inflammation of the colon and is often used to describe an inflammation of the large intestine .Colitides may be acute and self-limited or chronic, i.e...
, ischemia reperfusion injury
Reperfusion injury
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and...
and sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
. In fact, animal models of colitis, ischemia re-perfusion and sepsis related gut dysfunction have been shown to be benefited with therapeutic doses of ghrelin. It has also been shown to have regenerative capacity and is beneficial in case of mucosal injury to the stomach. Ghrelin also enhances the motility of gastrointestinal tract, as does motilin
Motilin
Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the MLN gene.Motilin is secreted by endocrine M cells that are numerous in crypts of the small intestine, especially in the duodenum and jejunum. Based on amino acid sequence, motilin is unrelated...
. Ghrelin also appears to promote gastrointestinal and pancreatic malignancy.
Lung development
In fetuses, it seems that ghrelin is produced early by the lung and promotes growth.Learning and memory
Animal modelAnimal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s indicate that ghrelin may enter the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
from the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
stream, altering nerve-cell
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
connections
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
, and so enhancing learn
LEARN
LEARN may refer to:* Law Enforcement Agency Resource Network, a website run by the Anti-Defamation League* LEARN diet, a brand name diet product...
ing and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
. It is suggested that learning may be best during the day and when the stomach is empty, since ghrelin levels are higher at these times. The team of the Yale School of Medicine
Yale School of Medicine
The Yale School of Medicine at Yale University is a private medical school located in New Haven, Connecticut, U.S. It was founded in 1810 as The Medical Institution of Yale College, and formally opened its doors in 1813....
also noted that a similar effect for human neural
Neurophysiology
Neurophysiology is a part of physiology. Neurophysiology is the study of nervous system function...
-physiology
Physiology
Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...
is quite plausible. In rodents, X/A-like cells produce ghrelin.
Stress-induced depression
The hormone might help defend against symptoms of stress-induced depressionDepression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. To test whether ghrelin could regulate depressive symptoms brought on by chronic stress
Chronic stress
Chronic stress is the response to emotional pressure suffered for a prolonged period over which an individual perceives he or she has no control. It involves an endocrine system response in which occurs a release of corticosteroids...
, the researchers subjected mice to daily bouts of social stress, using a standard laboratory technique that induces stress by exposing normal mice to very aggressive “bully” mice. Such animals have been shown to be good models for studying depression in humans. The researchers stressed both wild-type mice and altered mice that were unable to respond to ghrelin. They found that, after experiencing stress, both types of mice had significantly elevated levels of ghrelin that persisted at least four weeks after their last defeat encounter. The altered mice, however, displayed significantly greater social avoidance than their wild-type counterparts, indicating an exacerbation of depression-like symptoms. They also ate less than the wild-type mice.
Sleep-Duration
A study appearing in the journal PLoS MedicinePLoS Medicine
PLoS Medicine is a peer-reviewed medical journal covering the full spectrum of the medical sciences. It began operation on October 19, 2004. It was the second journal of the Public Library of Science , a non-profit open-access publisher. All content in PLoS Medicine is published under the Creative...
suggests that short sleep duration is associated with high levels of ghrelin and obesity; ghrelin appears to be a factor contributing to the short sleep duration and obesity. Scientists have uncovered an inverse relationship between the hours of sleep and blood plasma concentrations of ghrelin; as the hours of sleep increase, ghrelin concentrations were considerably lower, thereby potentially reducing appetite and avoiding potential obesity.
Clinical significance
Ghrelin levels in the plasma of obeseObesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
individuals are lower than those in leaner individuals thus suggesting that ghrelin does not contribute to obesity, except in the cases of Prader-Willi syndrome
Prader-Willi syndrome
Prader–Willi syndrome is a rare genetic disorder in which seven genes on chromosome 15 are deleted or unexpressed on the paternal chromosome...
-induced obesity where high ghrelin levels are correlated with increased food intake . Those suffering from the eating disorder anorexia nervosa
Anorexia nervosa
Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...
have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls.. The use of Ghrelin on Anorexia Nervosa patients has been shown to increase food intake by 12-36% over the trial period.
Yildiz and colleagues found that the level of ghrelin increases during the time of day from midnight to dawn in thinner people, suggesting a flaw in the circadian
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
system of obese individuals. Professor Cappuccio of the University of Warwick
University of Warwick
The University of Warwick is a public research university located in Coventry, United Kingdom...
has recently discovered that short sleep
Sleep
Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces ghrelin, which stimulates appetite and creates less leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
, which, among its many other effects, suppresses appetite.
Ghrelin levels are also high in patients that have cancer-induced cachexia
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
.
At least one study found that gastric bypass surgery not only reduces the gut's capacity for food but also dramatically lowers ghrelin levels compared to both lean controls and those that lost weight through dieting alone.
Ghrelin through its receptor increases the concentration of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
, a region of the brain where dopamine cell degeneration leads to Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. Hence ghrelin may find application in slowing down the onset of Parkinson's disease.