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Ghrelin: a new player in the control of gastrointestinal functions

2005; BMJ; Volume: 54; Issue: 11 Linguagem: Inglês

10.1136/gut.2004.062604

1468-3288

T. L. Peeters,

Diet and metabolism studies

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R), present on pituitary cells secreting growth hormone.Ghrelin and motilin, and GHS-R and the motilin receptor, are structurally related.Surprisingly, ghrelin is most abundant in the stomach, and GHS-R is also present in the stomach and in other organs and tissues, suggesting effects beyond stimulation of growth hormone in the pituitary, and in particular in the regulation of gastrointestinal function.However, as yet ghrelin seems rather a signal by which the digestive system regulates functions other than the digestive process itself.The most important role of ghrelin appears to be stimulation of appetite and regulation of energy homeostasis, favouring adiposity, and thus contributing to obesity.As recently suggested, ghrelin may therefore be called the ''saginary'' (fattening) peptide.Ghrelin may affect gastric acid secretion and gastroprotection but the suggested role of ghrelin in Helicobacter pylori infection implicates again the saginary effect.Ghrelin is functionally related to motilin as it also stimulates gastrointestinal motility.In rodents, ghrelin may have taken over the function of motilin, as rodents are natural motilin knockouts.Ghrelin appears to be an endocrine signal, possibly reaching the central nervous system via the bloodstream.However, it also uses neural pathways, in particular the vagus.A better understanding of the physiology of ghrelin may lead to new therapeutic approaches in the treatment of obesity and hypomotility syndromes. CASABLANCA REVISITEDThe hypothalamus has been called the ''Casablanca of the central nervous system.''A place ''plenty of intrigue … where mysterious messages from the brain are sorted out and scrambled into a new language of peptide hormones''. 1 It is the language of the releasing hormones which start a signalling cascade first to the pituitary then via the tropins to the endocrine glands and by way of the hormones to the different organs and tissues.The story of the identification of the first one, thyrotropin releasing hormone, in 1969, has some of the qualities of the 1943 classic spy movie ''Casablanca,'' to which the quote refers.The process which led to the discovery of ghrelin, as yet the last one, also went through a few unexpected turns.The hypothalamus is where it all started.In 1976, in an effort to learn more about the elusive hypothalamic factor responsible for stimulation of growth hormone secretion by the pituitary, the endocrinology group led by Bowers at Tulane University in New Orleans started to develop synthetic peptides, analogues of the enkephalins, as these were known to be weak growth hormone releasers.A similar strategy had been part of the search for thyrotropin releasing hormone.Eventually, compounds were synthesised, such as hexarelin and ''growth hormone releasing peptide-6'' (GHRP-6), devoid of opioid activity, but potent releasers of growth hormone from the pituitary.They became known as growth hormone secretagogues (GHSs).When growth hormone releasing hormone (GHRH) was isolated in 1982, interest in GHSs declined until it was realised in 1984 that GHSs act via a receptor other than GHRH.This stimulated the pharmaceutical industry to develop non-peptide GHSs and one of them, MK-0677, enabled the MSD group led by R Smith to clone the GHS receptor (GHS-R) in 1996.An extensive review of these developments was written in 1998 by Bowers who played a most prominent role in it. 2