Metabolism Without Modification

Science Signaling  21 Dec 2010:
Vol. 3, Issue 153, pp. ec390
DOI: 10.1126/scisignal.3153ec390

Obesity-associated metabolic disease has rapidly become a public health priority in the developed world and is being addressed through prevention strategies aimed at life-style changes and through pharmacological approaches. Barnett et al. designed a drug that inhibits the action of ghrelin, a circulating peptide hormone that increases fat mass and food intake. The drug, a bisubstrate analog called GO-CoA-Tat, is a selective antagonist of ghrelin O-acyltransferase (GOAT), an enzyme that catalyzes a posttranslational modification that is essential for ghrelin activity. Injection of GO-CoA-Tat into wild-type mice on a high-fat diet improved glucose tolerance and reduced weight gain, probably through changes in metabolic activity. Because GO-CoA-Tat is a peptide-based drug that requires repeated injection, it is unsuitable for clinical use, but GOAT does represent a potentially valuable target for future drug development efforts in metabolic disease.

B. P. Barnett, Y. Hwang, M. S. Taylor, H. Kirchner, P. T. Pfluger, V. Bernard, Y.-y. Lin, E. M. Bowers, C. Mukherjee, W.-J. Song, P. A. Longo, D. J. Leahy, M. A. Hussain, M. H. Tschöp, J. D. Boeke, P. A. Cole, Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science 330, 1689–1692 (2010). [Abstract] [Full Text]