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      Obestatin, Acylated and Total Ghrelin Concentrations in the Perinatal Rat Pancreas

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          Abstract

          Background: Ghrelin and obestatin are encoded by the preproghrelin gene and originate from posttranslational processing of the preproghrelin peptide. The fetal rat pancreas contains acylated and desacylated ghrelin peptides, as well as growth hormone secretagogue receptor -1a mRNA. Acylated ghrelin inhibits insulin secretion. We investigated the plasma and tissue ontogeny of ghrelin and obestatin in the rat. Methods: We measured obestatin and acylated and total ghrelin concentrations in plasma, pancreas and stomach from rat fetuses (F20) and neonates at postnatal day (PN) 1, 6, 12 and 21). Results: Overall, obestatin concentrations were markedly lower than total ghrelin concentrations. In plasma, total ghrelin concentrations decreased abruptly after birth (p < 0.05), contrasting with a 3 times increase in the concentration of acylated ghrelin between F20 and PN1 (p < 0.05). In pancreas, total ghrelin and obestatin concentrations decreased progressively from PN1 to PN21 but acylated ghrelin concentrations increased 6–7 times from F20 (18 [6] pg/ml) to PN6 (122 [59] pg/ml). The percent of acylated ghrelin increased from 1.8 (0.6) at F20 to 39.7 (13.0) % of total ghrelin immunoreactivity at PN12 (p < 0.05). There were significant positive correlations between postnatal obestatin, acylated or total ghrelin and insulin concentrations in the pancreas (all p < 0.02, r<sup>2</sup> > 0.21) and between postnatal total ghrelin and obestatin (in pancreas, r<sup>2</sup> = 0.37) or acylated ghrelin (in stomach, r<sup>2</sup> = 0.27) (p < 0.001). Conclusion: Ghrelin and obestatin are present in the perinatal pancreas where they could potentially affect insulin secretion.

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          Most cited references 18

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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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              High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist.

              Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity; however, upon agonist stimulation the motilin receptor signaled as strongly as the unstimulated ghrelin receptor. It is concluded that the ghrelin receptor is highly constitutively active and that this activity could be of physiological importance in its role as a regulator of both GH secretion and appetite control. It is suggested that inverse agonists for the ghrelin receptor could be particularly interesting for the treatment of obesity.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2006
                July 2006
                26 July 2006
                : 66
                : 2
                : 81-88
                Affiliations
                aEndocrinology and Diabetes Unit, British Columbia’s Children’s Hospital, University of British Columbia, Vancouver, Canada; bEndocrinology Unit, Hospital Infantil Niño Jesús, Universitad Autónoma de Madrid, Madrid, Spain
                Article
                93585 Horm Res 2006;66:81–88
                10.1159/000093585
                16733368
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, References: 26, Pages: 8
                Categories
                Original Paper

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