Ghrelin—a hormone with multiple functions

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Abstract

Ghrelin is brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach mucosa but it is also expressed widely in different tissues and therefore may have both endocrine and paracrine effects. Ghrelin is the endogenous ligand of the G protein-coupled growth hormone secretagogue receptor. In the current review we comprehensively summarize (i) the data available regarding the structure, expression pattern and regulation of ghrelin and its receptor; (ii) the available information regarding the effect of ghrelin on the pituitary hormone axis, appetite regulation, cardiac and gastrointestinal function, carbohydrate metabolism, adipose and reproductive tissue, cell proliferation and behavioral effects; (iii) experimental and clinical data regarding circulating ghrelin levels observed in various physiological and pathological conditions; and (iv) data on gene variations of ghrelin and its receptor. It is apparent that ghrelin is involved in many more processes than originally envisaged, and in particular appears to have relatively less relevance to growth hormone physiology and more to the regulation of energy fluxes in the organism. Increasing data link ghrelin to the overall control of energy use and flow in situations where there is a limitation of energy sources and ghrelin appears to play a pivotal role in energy homeostasis.

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.

References (492)

  • G Bisi et al.

    Cardiac effects of hexarelin in hypopituitary adults

    Eur. J. Pharmacol.

    (1999)
  • L Brunetti et al.

    Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release in the hypothalamus

    Eur. J. Pharmacol.

    (2002)
  • V.P Carlini et al.

    Ghrelin increases anxiety-like behavior and memory retention in rats

    Biochem. Biophys. Res. Commun.

    (2002)
  • L Chang et al.

    Therapeutic effects of ghrelin on endotoxic shock in rats

    Eur. J. Pharmacol.

    (2003)
  • J Cheng et al.

    Growth hormone releasing peptides: a comparison of the growth hormone releasing activities of GHRP-2 and GHRP-6 in rat primary pituitary cells

    Life Sci.

    (1997)
  • E.E Codd et al.

    Binding of growth hormone-releasing hexapeptide to specific hypothalamic and pituitary binding sites

    Neuropharmacology

    (1989)
  • M.A Cowley

    Hypothalamic melanocortin neurons integrate signals of energy state

    Eur. J. Pharmacol.

    (2003)
  • M.A Cowley et al.

    Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat

    Neuron

    (1999)
  • M.A Cowley et al.

    The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis

    Neuron

    (2003)
  • E.F Adams et al.

    In vitro responses of GH-secreting tumours with and without gsp oncogenes to octreotide, GHRH and growth hormone-releasing peptide

  • E.F Adams et al.

    Presence of growth hormone secretagogue receptor messenger ribonucleic acid in human pituitary tumors and rat GH3 cells

    J. Clin. Endocrinol. Metab.

    (1998)
  • E.F Adams et al.

    Protein kinase C-dependent growth hormone releasing peptides stimulate cyclic adenosine 3,5-monophosphate production by human pituitary somatotropinomas expressing gsp oncogenes: evidence for cross-talk between transduction pathways

    Mol. Endocrinol.

    (1996)
  • E.F Adams et al.

    Biochemical characteristics of human pituitary somatotrophinomas with or without gsp mutations

    J. Clin. Endocrinol. Metab.

    (1995)
  • E Adeghate et al.

    Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats

    J. Neuroendocrinol.

    (2002)
  • G Aimaretti et al.

    Endocrine responses to ghrelin in adult patients with isolated childhood-onset growth hormone deficiency

    Clin. Endocrinol. (Oxf.)

    (2002)
  • M.S Akman et al.

    Mechanisms of action of a second generation growth hormone-releasing peptide (Ala-His-d-beta-Nal-Ala-Trp-d-Phe-Lys-NH2) in rat anterior pituitary cells

    Endocrinology

    (1993)
  • C Anderwald et al.

    Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients

    Diabetes

    (2003)
  • J Argente et al.

    Sexual dimorphism of growth hormone-releasing hormone and somatostatin gene expression in the hypothalamus of the rat during development

    Endocrinology

    (1991)
  • H Ariyasu et al.

    Delayed short-term secretory regulation of ghrelin in obese animals: evidenced by a specific ria for the active form of ghrelin

    Endocrinology

    (2002)
  • H Ariyasu et al.

    Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans

    J. Clin. Endocrinol. Metab.

    (2001)
  • M Arosio et al.

    Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels

    J. Clin. Endocrinol. Metab.

    (2003)
  • E Arvat et al.

    Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans

    J. Endocrinol. Invest.

    (2000)
  • E Arvat et al.

    Oestrogen replacement does not restore the reduced GH-releasing activity of Hexarelin, a synthetic hexapeptide, in post- menopausal women

    Eur. J. Endocrinol.

    (1997)
  • E Arvat et al.

    Endocrine activities of ghrelin, a natural GH secretagogue, in humans: comparison and interactions with hexarelin, a non natural peptidyl GHS, and GH-releasing hormone

    J. Clin. Endocrinol. Metab.

    (2001)
  • E Arvat et al.

    Adrenocorticotropin and cortisol hyperresponsiveness to hexarelin in patients with Cushing's disease bearing a pituitary microadenoma, but not in those with macroadenoma

    J. Clin. Endocrinol. Metab.

    (1998)
  • A Asakawa et al.

    Antagonism of ghrelin receptor reduces food intake and body weight gain in mice

    Gut

    (2003)
  • A Asakawa et al.

    A role of ghrelin in neuroendocrine and behavioral responses to stress in mice

    Neuroendocrinology

    (2001)
  • M Bagnasco et al.

    Evidence for the existence of distinct central appetite, energy expenditure, and ghrelin stimulation pathways as revealed by hypothalamic site-specific leptin gene therapy

    Endocrinology

    (2002)
  • M Bagnasco et al.

    Ghrelin and leptin pulse discharge in fed and fasted rats

    Endocrinology

    (2002)
  • A.R.T Bailey et al.

    Chronic central infusion of growth hormone secretagogues: effects on fos expression and peptide gene expression in the rat arcuate nucleus

    Neuroendocrinology

    (1999)
  • G Baldanzi et al.

    Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT

    J. Cell Biol.

    (2002)
  • W.A Banks et al.

    Extent and direction of ghrelin transport across the blood–brain barrier is determined by its unique primary structure

    J. Pharmacol. Exp. Ther.

    (2002)
  • A.L Barkan et al.

    Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels

    J. Clin. Endocrinol. Metab.

    (2003)
  • M.L Barreiro et al.

    Cellular location and hormonal regulation of ghrelin expression in rat testis

    Biol. Reprod.

    (2002)
  • M.L Barreiro et al.

    Expression and homologous regulation of GH secretagogue receptor mRNA in rat adrenal gland

    Eur. J. Endocrinol.

    (2002)
  • R.L Batterham et al.

    Inhibition of food intake in obese subjects by peptide YY3-36

    N. Engl. J. Med.

    (2003)
  • R.L Batterham et al.

    Gut hormone PYY(3-36) physiologically inhibits food intake

    Nature

    (2002)
  • R.L Batterham et al.

    Pancreatic polypeptide reduces appetite and food intake in humans

    J. Clin. Endocrinol. Metab.

    (2003)
  • N.J Beaumont et al.

    Ghrelin can bind to a species of high-density lipoprotein associated with paraoxonase

    J. Biol. Chem.

    (2003)
  • M.A Bednarek et al.

    Structure and function studies on the new growth hormone releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a

    J. Med. Chem.

    (2000)
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