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Evidence that Intestinal Glucagon-Like Peptide-1 Plays a Physiological Role in Satiety

Department of Psychology (D.L.W.), Florida State University, Tallahassee, Florida 32306-4301; and Diabetes and Obesity Center of Excellence (M.W.S.) and Department of Medicine (D.G.B., M.W.S.), Division of Metabolism, Endocrinology, and Nutrition, and Department of Biological Structure (D.G.B.), University of Washington, and Research and Development Service (D.G.B.), Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108

Address all correspondence and requests for reprints to: Diana L. Williams, B328, PDB, Department of Psychology, 1107 West Call Street, Florida State University, Tallahassee, Florida 32306-4301. E-mail: williams{at}psy.fsu.edu.

A physiological role in satiety is proposed for glucagon-like peptide-1 (GLP-1), secreted by the distal intestine in response to ingested nutrients. Here we report that in rats, ip injection of the GLP-1 receptor (GLP-1-R) antagonist exendin 9-39 (Ex9) elicited hyperphagia, but only at times of day when intake is otherwise low. Furthermore, ip administration of Ex9 attenuated satiety induced by either a voluntarily consumed sucrose meal (by 100%) or an intragastric glucose load (by 40%). To determine whether these effects involve blockade of GLP-1-R in brain or at a peripheral site, we injected Ex9 either centrally (into the third ventricle) or peripherally (ip) prior to GLP-1 injected either centrally or peripherally. Anorexia induced by peripheral GLP-1 was fully blocked by peripheral, but not central, pretreatment with Ex9, whereas the opposite was true for anorexic effect of central GLP-1. Thus, ip Ex9 appears to attenuate satiety via peripheral GLP-1-R blockade. Finally, anorexia induced by ip injection of exendin-4 (a GLP-1-R agonist) was due to both reduced meal size and increased duration between meals. We conclude that GLP-1 released from the intestine in response to ingested nutrients is a physiologically active satiety signal.

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