Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor

Brad P. Barnett, You Sang Hwang, Martin S. Taylor, Henriette Kirchner, Paul T. Pfluger, Vincent Bernard, Yu Yi Lin, Erin M. Bowers, Chandrani Mukherjee, Woo Jin Song, Patti A. Longo, Daniel J. Leahy, Mehboob Hussain, Matthias H. Tschöp, Jef D. Boeke, Philip A. Cole

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1689-1692
Number of pages4
JournalScience
Volume330
Issue number6011
DOIs
StatePublished - Dec 17 2010

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Acyltransferases
Ghrelin
Weights and Measures
Glucose
Weight Gain
Peptides
Peptide Hormones
Metabolic Diseases
Post Translational Protein Processing
Vertebrates
Cultured Cells
Stomach

ASJC Scopus subject areas

  • General

Cite this

Barnett, B. P., Hwang, Y. S., Taylor, M. S., Kirchner, H., Pfluger, P. T., Bernard, V., ... Cole, P. A. (2010). Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science, 330(6011), 1689-1692. https://doi.org/10.1126/science.1196154

Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. / Barnett, Brad P.; Hwang, You Sang; Taylor, Martin S.; Kirchner, Henriette; Pfluger, Paul T.; Bernard, Vincent; Lin, Yu Yi; Bowers, Erin M.; Mukherjee, Chandrani; Song, Woo Jin; Longo, Patti A.; Leahy, Daniel J.; Hussain, Mehboob; Tschöp, Matthias H.; Boeke, Jef D.; Cole, Philip A.

In: Science, Vol. 330, No. 6011, 17.12.2010, p. 1689-1692.

Research output: Contribution to journalArticle

Barnett, BP, Hwang, YS, Taylor, MS, Kirchner, H, Pfluger, PT, Bernard, V, Lin, YY, Bowers, EM, Mukherjee, C, Song, WJ, Longo, PA, Leahy, DJ, Hussain, M, Tschöp, MH, Boeke, JD & Cole, PA 2010, 'Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor', Science, vol. 330, no. 6011, pp. 1689-1692. https://doi.org/10.1126/science.1196154
Barnett BP, Hwang YS, Taylor MS, Kirchner H, Pfluger PT, Bernard V et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science. 2010 Dec 17;330(6011):1689-1692. https://doi.org/10.1126/science.1196154
Barnett, Brad P. ; Hwang, You Sang ; Taylor, Martin S. ; Kirchner, Henriette ; Pfluger, Paul T. ; Bernard, Vincent ; Lin, Yu Yi ; Bowers, Erin M. ; Mukherjee, Chandrani ; Song, Woo Jin ; Longo, Patti A. ; Leahy, Daniel J. ; Hussain, Mehboob ; Tschöp, Matthias H. ; Boeke, Jef D. ; Cole, Philip A. / Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. In: Science. 2010 ; Vol. 330, No. 6011. pp. 1689-1692.
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