ReviewThe ghrelin axis in disease: Potential therapeutic indications
Section snippets
Physiology
Ghrelin is a 28 amino acid peptide hormone secreted predominantly from the stomach that acts to regulate appetite and metabolism. The ghrelin peptide has an unusual post-translational modification; an 8 or 10 carbon fatty acid is ester linked to serine 3. This acylation is unstable, and the majority of ghrelin seen in the circulation is in an unacylated form (Kojima et al., 1999). Only acylated ghrelin has biological activity at the known ghrelin receptor (Smith, 2005), though the des-acylated
Ghrelin assays
Circulating ghrelin is heterogeneous (see above) and labile to degradation by both proteases and especially by esterases in blood (Hosada et al., 2000, Liu et al., 2008). This results in a mixture of ghrelin forms and degradation products. Assays for ghrelin must first start with a sample preparation method where further degradation has been stabilized, and then must characterize which forms of ghrelin or its fragments will be detected.
Potential use of ghrelin or ghrelin antagonists in disease
A discussion about modulating ghrelin receptor action must consider 2 different therapeutic approaches: (a) enhancing ghrelin receptor action and (b) blocking ghrelin receptor action. The following review will address some of the studies published.
Conclusion
Several conditions such as CHF, ESKD, COPD, cancer and the sarcopenia of aging are associated with significant weight loss and increased protein breakdown, which ultimately lead to increased morbidity and mortality. Based on its orexigenic effects, ghrelin and ghrelin mimetics have been shown to be of potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions. Compared to ghrelin, ghrelin mimetics have the advantage that some can be given once daily and some are
References (64)
- et al.
Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment
Kidney Int.
(2009) - et al.
Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness
Biochem. Biophys. Res. Commun.
(2003) - et al.
Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cells
Biochem. Biophys. Res. Commun.
(2003) - et al.
Ghrelin treatment suppresses neutrophil-dominant inflammation in airways of patients with chronic respiratory infection
Pulm. Pharmacol. Ther.
(2008) - et al.
Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor
Trends Endocrinol. Metab.
(2001) - et al.
Ghrelin—a hormone with multiple functions
Front. Neuroendocrinol.
(2004) - et al.
Structure–activity relationship of ghrelin: pharmacological study of ghrelin peptides
Biochem. Biophys. Res. Commun.
(2001) - et al.
Treatment of cachexia with ghrelin in patients with COPD
Chest
(2005) - et al.
The aging population—is there a role for endocrine interventions?
Growth Horm. IGF Res.
(2009) - et al.
Grelin stimulates growth hormone secretion and food intake in aged rats
Mech. Ageing Dev.
(2007)
The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN073, a novel orally active growth hormone secretagogue in healthy male volunteers
Growth Horm. IGF Res.
The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture
J. Am. Geriatr. Soc.
Structure–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.
A synthetic pentapeptide which specifically releases GH, in vitro
Effects of ghrelin administration in frail and healthy older women
Ghrelin and cortistatin in lung cancer: expression of peptides and related receptors in human primary tumors and in vitro effect on the H345 small cell carcinoma cell line
J. Endocrinol. Invest.
Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults
J. Clin. Endocrinol. Metab.
Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile
Endocrinology
Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia
Endocrinology
Unacylated ghrelin rapidly modulates lipogenic and insulin signaling pathway gene expression in metabolically active tissues of GHSR deleted mice
PLOS One
Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells
J. Clin. Invest.
Small-molecule ghrelin receptor antagonist improve glucose tolerance, suppress appetite, and promote weight loss
Endocrinology
Ghrelin prevents cisplatin-induced mechanical hyperalgesia and cachexia
Endocrinology
A phase II, randomized, placebo-controlled, double blind study of the efficacy and safety of RC-1291 for the treatment of cancer-cachexia
J. Clin. Oncol.
SUN 11031 (synthetic human ghrelin) improves lean body mass and function in advanced COPD cachexia in a placebo controlled trial
Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newborn rats
J. Mol. Endocrinol.
Evaluation of the comparability of commercial ghrelin assays
Clin. Chem.
New active series of growth hormone secretagogues
J. Med. Chem.
Ghrelin octanoylation mediated by an orphan lipid transferase
Proc. Natl. Acad. Sci. U.S.A.
Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer
Proc. Natl. Acad. Sci. U.S.A.
Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue
Biochem. Biophys. Res. Commun.
Plasma levels of intact and degraded ghrelin and their responses to glucose infusion in anorexia nervosa
J. Clin. Endocrinol. Metab.
Cited by (33)
Behavioural characterization of ghrelin ligands, anamorelin and HM01: Appetite and reward-motivated effects in rodents
2020, NeuropharmacologyCitation Excerpt :The orexigenic effects of ghrelin are mediated via activation of its target G-protein coupled receptor, the GHSR-1a, which has been conclusively demonstrated across species (Wren et al., 2000; Cummings et al., 2001; Nagaya et al., 2001; Wren et al., 2001a,b; Mericq et al., 2003; Chen et al., 2004; Druce et al., 2005; Schmid et al., 2005; Wynne et al., 2005). As such, the GHSR-1a represents a promising therapeutic target for conditions of under-eating, associated with, for example, Cancer Anorexia Cachexia Syndrome (CACS) (Nass et al., 2011; Howick et al., 2017), but also with conditions of over-eating and obesity (Soares et al., 2008; Schellekens et al., 2010). Importantly, CACS causes extreme weight loss, muscle waste and reduced adipose tissue and it is only partially reversed by nutrition (Currow et al., 2018).
Is there a place for anabolic hormones in critical care?
2019, Evidence-Based Practice of Critical CareTriazole GHS-R1a antagonists JMV4208 and JMV3002 attenuate food intake, body weight, and adipose tissue mass in mice
2014, Molecular and Cellular EndocrinologyCitation Excerpt :Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R1a), is a linear 28-amino-acid peptide with an n-octanoyl group on the Ser3 residue and is predominantly produced by the stomach (Kojima et al., 1999). Ghrelin is the only known orexigenic hormone produced in the periphery (Nass et al., 2011) and directly enhances both expression and secretion of the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (Cowley et al., 2003; Kojima and Kangawa, 2005). Ghrelin promotes positive energy balance, serving as a short-term hunger signal and a long-term adiposity signal (Nakazato et al., 2001; Tschöp et al., 2000).
Induced ablation of ghrelin cells in adult mice does not decrease food intake, body weight, or response to high-fat diet
2014, Cell MetabolismCitation Excerpt :It requires octanoylation on Ser3 by Ghrelin-O-acyltransferase (GOAT) (Yang et al., 2008; Gutierrez et al., 2008) in order to interact with its receptor, the growth hormone secretogogue receptor (GHSR), which is present in tissues throughout the body, including the pituitary and hypothalamus (Cruz and Smith, 2008). The discovery that ghrelin administration stimulates appetite in rodents (Tschöp et al., 2000) and humans (Wren et al., 2001) led to the hypothesis that ghrelin is an orexigenic antipode to anorexigenic leptin and raised hopes that pharmacologic inhibition of ghrelin would prove useful for curbing appetite and treating obesity (Cummings, 2006; Nass et al., 2011). The argument that ghrelin functions in vivo as an appetite-stimulating hormone was bolstered by evidence that its plasma concentration peaks before meals and falls shortly after feeding (Cummings et al., 2001; Tschöp et al., 2001; Nass et al., 2008) and that some forms of bariatric surgery—until recently, the only FDA-approved treatment for reducing appetite—suppress ghrelin levels (Cummings et al., 2002), although the latter observation has been challenged (Saliba et al., 2009).
Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor
2013, Bioorganic and Medicinal Chemistry LettersIdentification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor
2012, Bioorganic and Medicinal Chemistry LettersCitation Excerpt :More recently interest has turned to the opposite functional profile. Although some aspects of the switch to functional antagonists are controversial,5 the change has been driven by a steady stream of supporting evidence suggesting that ligand neutralization6,7 or receptor deletion8,9 can have beneficial effects on body weight and glucose homeostasis.10–12 Accompanying the move in functional profile to antagonists or inverse agonists is a decision to target a centrally acting agent capable of reaching receptors in the hypothalamus, or to target an agent that is more peripherally restricted.