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, r2 > 0.21) and between postnatal total ghrelin and obestatin (in pancreas, r2 = 0.37) or acylated ghrelin (in stomach, r2 = 0.27) (p < 0.001). Conclusion: Ghrelin and obestatin are present in the perinatal pancreas where they could potentially affect insulin secretion.

Keywords:
Pancreas, Obestatin, Acylated ghrelin, Desacylated ghrelin, Fetus, Neonate, Insulin
1.
Ariyasu H, Takaya K, Tagami T, 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;86:4753–4758.
2.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–660.
3.
Sun Y, Wang P, Zheng H, Smith RG: Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 2004;101:4679–4684.
4.
Thompson NM, Gill DA, Davies R, et al: Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004;145:234–242.
5.
Tschop M, Smiley DL, Heiman ML: Ghrelin induces adiposity in rodents. Nature 2000;407:908–913.
6.
van der Lely AJ, Tschop M, Heiman ML, Ghigo E: Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004;25:426–457.
7.
Chanoine JP, Wong AC: Ghrelin gene expression is markedly higher in fetal pancreas compared with fetal stomach: effect of maternal fasting. Endocrinology 2004;145:3813–3820.
8.
Hosoda H, Kojima M, Matsuo H, Kangawa K: Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000;279:909–913.
9.
Chanoine JP, Yeung LP, Wong AC: Umbilical cord ghrelin concentrations in asian and caucasian neonates. Horm Res 2003;60:116–120.
10.
Farquhar J, Heiman M, Wong AC, Wach R, Chessex P, Chanoine JP: Elevated umbilical cord ghrelin concentrations in small for gestational age neonates. J Clin Endocrinol Metab 2003;88:4324–4327.
11.
Chanoine JP, Yeung LP, Wong AC, Birmingham CL: Immunoreactive ghrelin in human cord blood: relation to anthropometry, leptin, and growth hormone. J Pediatr Gastroenterol Nutr 2002;35:282–286.
12.
Wierup N, Yang S, McEvilly RJ, Mulder H, Sundler F: Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells. J Histochem Cytochem 2004;52:301–310.
13.
Chanoine JP: Ghrelin in growth and development. Horm Res 2005;63:129–138.
14.
Zhang J, Ren PV, Avsian-Kretchmer O, et al: Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 2005;310:996–999.
15.
Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW: High constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist. Mol Endocrinol 2003;17:2201–2210.
16.
Holst B, Holliday ND, Bach A, Elling CE, Cox HM, Schwartz TW: Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 2004;279: 53806–53817.
17.
Toshinai K, Mondal MS, Nakazato M, et al: Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem Biophys Res Commun 2001;281:1220–1225.
18.
Neary NM, Druce MR, Small CJ, Bloom SR: Acylated ghrelin stimulates food intake in the fed and fasted states but desacylated ghrelin has no effect. Gut 2006;55:135.
19.
Nishi Y, Hiejima H, Mifune H, Sato T, Kangawa K, Kojima M: Developmental changes in the pattern of ghrelin’s acyl modification and the levels of acyl-modified ghrelins in murine stomach. Endocrinology 2005;146:2709–2715.
20.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–660.
21.
Heller RS, Jenny M, Collombat P, et al: Genetic determinants of pancreatic epsilon-cell development. Dev Biol 2005;286:217–224.
22.
Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L: Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA 2004;101:2924–2929.
23.
Kaung HL: Growth dynamics of pancreatic islet cell populations during fetal and neonatal development of the rat. Dev Dyn 1994;200:163–175.
24.
Finegood DT, Scaglia L, Bonner-Weir S: Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 1995;44:249–256.
25.
Svenstrup K, Skau M, Pakkenberg B, Buschard K, Bock T: Postnatal development of beta-cells in rats. Proposed explanatory model. APMIS 2002;110:372–378.
26.
Reimer MK, Pacini G, Ahren B: Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology 2003;144:916–921.
© 2006 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
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.
You do not currently have access to this content.