Ghrelin

Ghrelin is a 28 amino-acid peptide, a member of the group of growth hormone secretagogues (GHSs). Ghrelin is mainly produced by the oxyntic glands of the gastric mucosa in the stomach. Majority of ghrelin in circulation and tissues is in inactive form, desacyl-ghrelin. Ghrelin O-acyltransferase (GOAT) catalyses octanoylation of the peptide, making the active form, acyl-ghrelin, which can activate ghrelin receptor (Kojima et al., 1999; Zhao et al., 2010). Inhibition of GOAT blocks ghrelin signalling.

In the anterior pituitary gland the peripherally produced acyl-ghrelin dose-dependently induces the release of the growth hormone (GH), and generally has anabolic effects. Hypothalamic GH-releasing hormone (GHRH) is another regulator of GH release. Acyl-ghrelin increases appetite, enhances gastric acid secretion and gastric motility, modulates stress and anxiety, sleep/wake cycle, glucose metabolism, insulin secretion, lipogenesis, and BAT thermogenesis (Colldén et al., 2017; Giorgioni et al., 2022). Desacyl-ghrelin cannot activate ghrelin-receptor, but may otherwise induce some effects, even opposite to acyl-ghrelin.

Fasting increases ghrelin plasma concentration, and feeding decreases it. Plasma concentration is low in obese people and high in lean people.

Ghrelin receptor GHS-R1a

Octanoylated acyl-ghrelin can activate growth hormone secretagogue receptor GHS-R1a, which is a G protein-coupled receptor (GPCR) consisting of 366 amino acid residues (Davenport et al., 2005). GHS-R1b is an inactive splicing variant of GHS-R1a. GHS-R1a can form homodimers and heterodimers with other GPCRs, including GHS-R1b, 5-HT2CR, D1R and D2R, SSTR5, orexin OX1 receptor, melanocortin MC3 receptor, and CB2R (Giorgioni et al., 2022).

GHS-R1a is found in the cardiovascular system, spleen, pancreas, adrenal glands, and kidneys (Gnanapavan et al., 2002; Colldén et al., 2017). In the heart, ghrelin may have cardioprotective activity (Baldanzi et al., 2002). Ghrelin stimulates lipogenesis in hepatocytes (Yin et al., 2021).

GHS-R1a is highly expressed in the pituitary gland, and in CNS, especially in hypothalamus and substantia nigra. Ghrelin induces anticonvulsant and neuroprotective effects and controls food anticipation and rewarding properties of food via GHS-R1a.

LEAP2 is an endogenous peptide antagonist of GHS-R1a (Ge et al., 2018).

PET

GHS-R1a agonists, antagonist, and inverse agonists, and GOAT inhibitors, have been developed as potential therapeutics (Giorgioni et al., 2022). Derivative compounds labelled with positron-emitting isotopes have been developed for PET imaging of ghrelin pathway (Childs et al., 2020; Bergmann et al., 2021).


See also:


Literature

Bergmann R, Chollet C, Els-Heindl S, Ullrich M, Berndt N, Pietzsch J, Máthé D, Bachmann M, Beck-Sickinger AG. Development of a ghrelin receptor inverse agonist for positron emission tomography. Oncotarget 2021; 12(5): 450-474. doi: 10.18632/oncotarget.27895.

Childs MD, Luyt LG. A decade's progress in the development of molecular imaging agents targeting the growth hormone secretagogue receptor. Mol Imaging. 2020; 19: 1-15. doi: 10.1177/1536012120952623.

Colldén G, Tschöp MH, Müller TD. Therapeutic potential of targeting the ghrelin pathway. Int J Mol Sci. 2017; 18(4): 798. doi: 10.3390/ijms18040798.

Davis J. Hunger, ghrelin and the gut. Brain Res. 2018; 1693: 154-158. doi: 10.1016/j.brainres.2018.01.024.

Giorgioni G, Del Bello F, Quaglia W, Botticelli L, Cifani C, Micioni Di Bonaventura E, Micioni Di Bonaventura MV, Piergentili A. Advances in the development of nonpeptide small molecules targeting ghrelin receptor. J Med Chem. 2022; 65(4): 3098-3118. doi: 10.1021/acs.jmedchem.1c02191.

Kishimoto I, Tokudome T, Hosoda H, Miyazato M, Kangawa K. Ghrelin. In: Handbook of Biologically Active Peptides. Elsevier, 2013. doi: 10.1016/B978-0-12-385095-9.00191-3.



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Updated at: 2023-02-01
Created at: 2023-01-15
Written by: Vesa Oikonen