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Science 330 (6011): 1689-1692

Copyright © 2010 by the American Association for the Advancement of Science

Glucose and Weight Control in Mice with a Designed Ghrelin O-Acyltransferase Inhibitor

Brad P. Barnett,1,2,* Yousang Hwang,1,* Martin S. Taylor,1,2,* Henriette Kirchner,3,7 Paul T. Pfluger,3 Vincent Bernard,2 Yu-yi Lin,2,6 Erin M. Bowers,1 Chandrani Mukherjee,1 Woo-Jin Song,4 Patti A. Longo,5 Daniel J. Leahy,5 Mehboob A. Hussain,4 Matthias H. Tschöp,3,7 Jef D. Boeke,2,{dagger} Philip A. Cole1,{dagger},{ddagger}

Abstract: Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser3, an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.

1 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 Department of Molecular Biology and Genetics and High Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Obesity Research Center, Metabolic Diseases Institute, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45237, USA.
4 Metabolism Division, Departments of Pediatrics, Medicine, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6 Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
7 Department of Pharmacology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: pcole{at}

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M. Bando, H. Iwakura, H. Ariyasu, H. Koyama, K. Hosoda, S. Adachi, K. Nakao, K. Kangawa, and T. Akamizu (2013)
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Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis.
P. J. D. Delhanty, M. Huisman, L. Y. Baldeon-Rojas, I. van den Berge, A. Grefhorst, T. Abribat, P. J. M. Leenen, A. P. N. Themmen, and A.-J. van der Lely (2013)
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MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin.
P. J. D. Delhanty, S. J. Neggers, and A. J. van der Lely (2012)
Eur. J. Endocrinol. 167, 601-608
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Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans.
A. Benso, D. H. St-Pierre, F. Prodam, E. Gramaglia, R. Granata, A. J. van der Lely, E. Ghigo, and F. Broglio (2012)
Eur. J. Endocrinol. 166, 911-916
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Mouse ghrelin-O-acyltransferase (GOAT) plays a critical role in bile acid reabsorption.
K. Kang, J. Schmahl, J.-M. Lee, K. Garcia, K. Patil, A. Chen, M. Keene, A. Murphy, and M. W. Sleeman (2012)
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Ghrelin Attenuates cAMP-PKA Signaling to Evoke Insulinostatic Cascade in Islet {beta}-Cells.
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