Ghrelin

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Ghrelin is a hormone produced mainly by P/D1 cells lining the fundus of the human stomach that stimulate 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. Ghrelin is also produced in the hypothalamic arcuate nucleus where it stimulates the secretion of growth hormone from the anterior pituitary gland. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.

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 is also made by a small population of neurons in the arcuate nucleus. 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.

Forms
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.

Role in disease
Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals. Those suffering from the eating disorder anorexia nervosa appear to have high plasma levels of ghrelin. These findings suggest that ghrelin does not cause anorexia or obesity, rather, ghrelin attempts to correct these disorders. 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. However, this study does not explain the low levels of Ghrelin found in the obese population. In the fetuses, it seems that ghrelin is early produced by the lung and promotes its growth. 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.

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.

Relation to obestatin
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 root ghre, meaning to grow.

Anti-obesity vaccine
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.