Ghrelin

Ghrelin is a hormone produced by P/D1 cells lining the fundus of the human stomach that stimulate appetite . In rodents, X/A-like cells produce ghrelin. The discovery of ghrelin was reported by Kojima et al. 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. Originally identified as the endogenous ligand for the 'growth hormone secretaguge (GHS) receptor, it was first thought to be mainly involved in the regulation of growth hormone secretion from the anterior pituitary gland.; however it was soon found to be a potent orexigen. Plasma concentrations of ghrelin increase progressively before meals and decrease after meals. In some respects it can be considered as a counterpart of the hormone leptin, produced by adipose tissue, which suppresses appetite. Receptors for ghrelin are expressed in the anterior pituitary and in several areas of the central nervous system, but at particularly high densities by neurons in the arcuate nucleus and the ventromedial hypothalamus. The ghrelin receptor is a G-protein coupled membrane receptor, formerly known as the GHS receptor (growth hormone secretagogue receptor). There is also evidence that ghrelin may also be made by a small population of neurons in the arcuate nucleus.

Ghrelin exists in an inactive (pure peptide) and an active (octanoylated) form (see Hexatropin). Other side chains than octanoyl were also observed.

Role in disease

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals. Yildiz et al (2004) 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.

Those suffering from the eating disorder anorexia nervosa appear to have high plasma levels of ghrelin. Ghrelin levels are also high in patients who have cancer-induced cachexia (Garcia et al, 2005).

Prader Willi Syndrome is another example of high levels of ghrelin, but here the ghrelin level 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 (Cummings et al, 2002).

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.

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.

References

• Garcia JM et al' (2005) Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia." J Clin Endocrinol Metab 90:2920-6. PMID 15713718.
• Yildiz BO et al. (2004) "Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity." Proc Natl Acad Sci U S A 101:10434-9. PMID 15231997.
• Cummings DE, et al. (2002) Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery. New England Journal of Medicine 346:1623-1630.
• Zhang JV et al. (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310:996-999. PMID 16284174.