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

Brad P. Barnett, Yousang 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 A. Hussain, Matthias H. Tschöp, Jef D. Boeke, Philip A. Cole

166 Citations (Scopus)


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
Issue number6011
Pages (from-to)1689-1692
Number of pages4
Publication statusPublished - 17.12.2010


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