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


Journal Article

Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser(3), 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.

Full Text

Cited Authors

  • Barnett, BP; Hwang, Y; Taylor, MS; Kirchner, H; Pfluger, PT; Bernard, V; Lin, Y-Y; Bowers, EM; Mukherjee, C; Song, W-J; Longo, PA; Leahy, DJ; Hussain, MA; Tschöp, MH; Boeke, JD; Cole, PA

Published Date

  • December 2010

Published In

Volume / Issue

  • 330 / 6011

Start / End Page

  • 1689 - 1692

PubMed ID

  • 21097901

Pubmed Central ID

  • 21097901

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1196154


  • eng