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      Is Ghrelin Synthesized in the Central Nervous System?

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          Abstract

          Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals.

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          Most cited references102

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          Ghrelin octanoylation mediated by an orphan lipid transferase.

          The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function.
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            Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake.

            Ghrelin, a circulating appetite-inducing hormone, is derived from a prohormone by posttranslational processing. On the basis of the bioinformatic prediction that another peptide also derived from proghrelin exists, we isolated a hormone from rat stomach and named it obestatin-a contraction of obese, from the Latin "obedere," meaning to devour, and "statin," denoting suppression. Contrary to the appetite-stimulating effects of ghrelin, treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain. Obestatin bound to the orphan G protein-coupled receptor GPR39. Thus, two peptide hormones with opposing action in weight regulation are derived from the same ghrelin gene. After differential modification, these hormones activate distinct receptors.
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              Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.

              Ghrelin, a novel peptide purified from stomach, is the endogenous ligand for the growth hormone secretagogue receptor and has potent growth hormone-releasing activity. The Ser3 residue of ghrelin is modified by n-octanoic acid, a modification necessary for hormonal activity. We established two ghrelin-specific radioimmunoassays; one recognizes the octanoyl-modified portion and another the C-terminal portion of ghrelin. Using these radioimmunoassay systems, we found that two major molecular forms exist-ghrelin and des-n-octanoyl ghrelin. While ghrelin activates growth-hormone secretagogue (GHS) receptor-expressing cells, the nonmodified des-n-octanyl form of ghrelin, designated as des-acyl ghrelin, does not. In addition to these findings, our radioimmunoassay systems also revealed high concentrations of ghrelin in the stomach and small intestine.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                15 March 2017
                March 2017
                : 18
                : 3
                : 638
                Affiliations
                [1 ]Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology (IMBICE), Universidad de La Plata-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comision de Investigaciones de la Provincia de Buenos Aires (CIC), Buenos Aires 1900, Argentina; agustinacabral177@ 123456hotmail.com
                [2 ]Department of Neuroscience, Brown University, Providence, RI 02912, USA; ejlopezsoto@ 123456gmail.com
                [3 ]Centre Psychiatrie & Neurosciences UMR_S894 INSERM Université Paris Descartes, 75014 Paris, France; jacques.epelbaum@ 123456inserm.fr
                [4 ]MECADEV UMR 7179 Centre National de la Recherche Scientifique, Muséum National d’Histoire Naturelle France, 91800 Brunoy, France
                Author notes
                [* ]Correspondence: mperello@ 123456imbice.gov.ar ; Tel.: +54-221-421-0112
                Article
                ijms-18-00638
                10.3390/ijms18030638
                5372651
                28294994
                e76bbeab-197e-4c4b-871a-4a3ca62694a8
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 07 February 2017
                : 10 March 2017
                Categories
                Review

                Molecular biology
                brain,neuron,acyl-ghrelin
                Molecular biology
                brain, neuron, acyl-ghrelin

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