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PNAS 104 (38): 15069-15074

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1

Hyeung-Jin Jang*, Zaza Kokrashvili{dagger}, Michael J. Theodorakis*, Olga D. Carlson*, Byung-Joon Kim*, Jie Zhou*, Hyeon Ho Kim*, Xiangru Xu*, Sic L. Chan*, Magdalena Juhaszova*, Michel Bernier*, Bedrich Mosinger{dagger}, Robert F. Margolskee{dagger},{ddagger}, and Josephine M. Egan*

*National Institute on Aging/National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224; and {dagger}Department of Neuroscience, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1065, New York, NY 10029

Communicated by Linda M. Bartoshuk, University of Florida, Gainesville, FL, July 23, 2007

Received for publication May 16, 2007.

Abstract: Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express {alpha}-gustducin. Ingestion of glucose by {alpha}-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from {alpha}-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses {alpha}-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for {alpha}-gustducin. We conclude that L cells of the gut "taste" glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut "taste cells" may provide an important treatment for obesity, diabetes and abnormal gut motility.

Key Words: enteroendocrine cells • gastrointestinal chemosensation • glucose sensor • incretin

Author contributions: H.-J.J., Z.K., and M.J.T. contributed equally to this work; H.-J.J., Z.K., M.J.T., B.M., R.F.M., and J.M.E. designed research; H.-J.J., Z.K., M.J.T., O.D.C., B.-J.K., J.Z., H.H.K., X.X., S.L.C., M.J., M.B., and B.M. performed research; M.J.T. contributed new reagents/analytic tools; H.-J.J., Z.K., M.J.T., O.D.C., B.-J.K., J.Z., H.H.K., X.X., S.L.C., M.J., M.B., B.M., R.F.M., and J.M.E. analyzed data; and H.-J.J., M.J.T., R.F.M., and J.M.E. wrote the paper.

Conflict of interest statement: Dr. Margolskee has a personal financial interest in the form of stock ownership in the Redpoint Bio company, receives consulting fees from the Redpoint Bio company, and is an inventor on patents and patent applications which have been licensed to the Redpoint Bio company.

This article contains supporting information online at www.pnas.org/cgi/content/full/0706890104/DC1.

{ddagger}To whom correspondence should be addressed. E-mail: robert.margolskee{at}mssm.edu

© 2007 by The National Academy of Sciences of the USA

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