Ghrelin—a hormone with multiple functions
Introduction
In 1977, Bowers reported that synthetic peptide analogues of the opiate met-enkephalin specifically released GH in vitro [50] (Fig. 1). Human data suggested that several peptide (growth hormone-releasing peptide (GHRP)-6, GHRP-1, GHRP-2, hexarelin, and ipamorelin) and later non-peptide compounds (L-692,429, MK-0677, NN703) have potent GH-releasing activity when administered parenterally or orally (MK-0677) (see review [245]). Computer-assisted overlays demonstrated that the peptide and non-peptide growth hormone secretagogues (GHSs) show three-dimensional similarities [387] and numerous synthetic GHS have since been synthesized by several companies [139], [175], [310], [342], [456]. Some of these have potent GH-releasing effects, good oral bioavailability, and negligible effects on other pituitary hormones [175], [368], [490]. In 1996, a specific G-protein coupled receptor was identified, the growth hormone secretagogue receptor (GHS-R), expressed mainly in the hypothalamus and pituitary [203]. This was soon followed by the discovery of an endogenous ligand for this receptor: ghrelin [240]. This “reverse pharmacology” is similar to the recognition and characterization of endogenous opiates or endocannabinoids [129], [329]. Surprisingly, ghrelin was originally identified from the stomach but it is also present in small amounts in the hypothalamus and therefore represents a new member of the brain–gut peptide family. Following earlier reports on positive effects on appetite of some GHSs [277], [326], [395], [445], the profound GH-independent weight-increasing and appetite effects of ghrelin were recognized [453]. The importance of ghrelin in body weight regulation was strengthened with the observation that circulating ghrelin levels show rapid as well as long-term changes: fasting increases circulating ghrelin levels, which drop after food intake [101], [454], while lean subjects have higher ghrelin levels than obese subjects [455]. In the current review, we will attempt to summarize the experimental and clinical data relating to the various aspects of ghrelin physiology and pathophysiology.
Section snippets
Ghrelin
In December 1999, an endogenous ligand of the GHS-R type 1a was first reported [240] (Fig. 2). The ligand was given the name ghrelin from the Proto-Indo-European word of `ghre,' which means grow, and `relin' as it had GH-releasing activities. Ghrelin is a 28 amino-acid peptide with a fatty acid chain modification on the N-terminal third amino acid. Interestingly, at the same time a stomach-derived mRNA sequence was identified coding for a protein with sequence similarities to motilin and named
Growth hormone secretagogue receptor
It was recognized in the early stages of GHS research that GHSs do not act via the known GHRH receptor. Specific binding sites have been detected in the pituitary and the hypothalamus in rats and pigs [88], [358], [392], [464]. Radiolabeled MK-0677 was shown to bind with high affinity and limited capacity to rat pituitary membranes [358], [357]. It was shown that the GHSs activated a G protein-coupled receptor since MK-0677 binding was Mg2+-dependent and was inhibited by GTP antagonists [81],
Effects of ghrelin
Ghrelin has been shown to affect a number of different systems including GH, ACTH and prolactin release, feeding, gastric acid secretion, gastric motility, and cell proliferation (Table 3). However, data from the recently described ghrelin knockout mice suggest that alternative pathways can compensate for many of the known effects of ghrelin (see below) [411].
Sex
The majority of the publications found no sex difference in circulating ghrelin levels [127], [362], [365], although some data suggest higher ghrelin levels in women [30], [396]. In a cross-sectional study of 120 subjects found significantly higher ghrelin levels in females, which persisted after controlling for age but lost significance after controlling waist–hip ratio and BMI [73]. Menopausal status did not influence ghrelin levels [365]. Higher ghrelin levels and stomach ghrelin mRNA
Knockout animal models
Ghrelin knockout animals are indistinguishable from their wild-type littermates [411]. In the ghrelin knockout animals, with no measurable circulating ghrelin, there is no difference in size, growth rate, body composition, food intake, reproduction, bone density, activity or behavior, blood chemistry, organ weight or tissue pathology. No difference was observed in food consumption in response to fasting, in response to ghrelin injection, leptin and insulin response to fasting and food intake
Ghrelin
We have identified 17 single nucleotide polymorphisms (SNPs) with sequencing of the exons, the exon–intron junctions, and 1 kb of the promoter [173]. The most common SNP changing an amino-acid in the prepro-ghrelin molecule is the Leu72Met change, with an allelic frequency for the Met ∼8% in Caucasian populations, followed by the Arg51Gln SNP with an allelic frequency of the Gln of 0.5–2% in different populations [460].
The Leu72Met polymorphism was reported to be associated with an earlier onset
Summary
Ghrelin is a peptide hormone secreted into the circulation from the stomach but also synthesized in a number of tissues suggesting both endocrine and paracrine effects. A special acyl modification of the peptide is necessary to some of its biological effects, such as GH release, but not for other effects, including cell proliferation in various cell types. While GHSs and ghrelin were originally considered as potent secretagogues of GH, a strong lipolytic hormone, ghrelin itself is lipogenic.
Acknowledgements
M.K. is supported by the Medical Research Council and M.G. by the Joint Research Board of St. Bartholomew's Hospital.
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