is a hormone
produced mainly by P/D1 cells
lining the fundus
of the human stomach
and epsilon cells of the pancreas
that stimulates appetite
. 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 also produced in the hypothalamic arcuate nucleus where it stimulates the secretion of growth hormone from the anterior pituitary gland.. Receptors for ghrelin are expressed by neurons in the arcuate nucleus and the ventromedial hypothalamus. The ghrelin receptor is a G protein-coupled receptor, formerly known as the GHS receptor (growth hormone secretagogue receptor).
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 kinases including Akt.
Ghrelin exists in an endocrinological inactive (pure peptide) and an active (octanoylated) form (see Hexatropin). Other side chains than octanoyl were also observed.
Mechanism of action
Ghrelin has emerged as the first 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 nucleus that include the orexigenic neuropeptide Y (NPY) neurones. Ghrelin-responsiveness of these neurones 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.
Roles of Ghrelin
- In the fetuses, it seems that ghrelin is early produced by the lung and promotes its growth.Learning and Memory
- Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, enhancing learning 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. In rodents, X/A-like cells produce ghrelin.Stress-Induced Depression
- A study appearing in the journal Nature Neuroscience (June 15, 2008 online) suggests that the hormone might help defend against symptoms of stress-induced depression 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.
Role in Disease
Ghrelin levels in the plasma of obese
individuals are lower than those in leaner individuals
except in the case of Prader-Willi syndrome
-induced obesity. Those suffering from the eating disorder anorexia nervosa
have high plasma levels of ghrelin compared to both the constitutionally thin and normal-weight controls
These findings suggest that ghrelin plays a role in both anorexia and obesity.
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, amongst its many other effects, suppresses appetite.
Ghrelin levels are also high in patients who have cancer-induced cachexia.
Prader-Willi syndrome is also characterized by high fasting levels of ghrelin; here the ghrelin levels are associated with high food intake.
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 who lost weight through dieting alone.
Relation to obestatin
is a hormone that was found, 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 purpose of this mechanism is unknown.
History and name
The discovery of ghrelin 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-European
, 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.
Recently Scripps research scientists have developed an anti-obesity vaccine, which is directed against the hormone ghrelin. The vaccine uses the immune system, specifically antibodies, to bind to selected targets, directing the body's own immune response against them. This prevents ghrelin from reaching the central nervous system, thus producing a desired reduction in weight gain.