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This version published online on June 12, 2008
Endocrinology, doi:10.1210/en.2008-0180
A more recent version of this article appeared on October 1, 2008
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Submitted on February 7, 2008
Accepted on June 5, 2008

Brain Glucagon-Like Peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance, and reduces energy expenditure

Claude Knauf, Patrice D. Cani, Afifa Ait-Belgnaoui, Alexandre Benani, Cédric Dray, Cendrine Cabou, André Colom, Marc Uldry, Sophie Rastrelli, Eric Sabatier, Natacha Godet, Aurélie Waget, Luc Pénicaud, Philippe Valet, and Rémy Burcelin*

Institut de Medecine Moleculaire de Rangueil (I2MR), INSERM U858, IFR31, Toulouse III University, CHU Rangueil, BP84225, 31432 Toulouse Cedex 4, France; Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université Catholique de Louvain, PMNT 73/69, Av E Mounier, Brussels, Belgium; Neuro-Gastroenterology and Nutrition Unit, UMR 1054 INRA/ESAP, 180 Chemin de Tournefeuille, BP 3, 31931 Toulouse Cedex 9, France; Laboratoire Métabolisme Plasticité Mitochondrie, Toulouse III University, CNRS UMR5241, BP84225, Toulouse, France; Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115

* To whom correspondence should be addressed. E-mail: burcelin{at}toulouse.inserm.fr.

Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin-resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a one month chronic blockage of brain GLP-1 signaling by Exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin-resistance in HFD mice. Furthermore, food intake was dramatically increased but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the Ex9 treatment. Thus we have demonstrated that in response to a high-fat diet, brain GLP-1 signaling induces hyperinsulinemia, insulin resistance, and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.
Key words: GLP-1 • diabetes • Exendin




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H.-R. Berthoud
Paying the Price for Eating Ice Cream: Is Excessive GLP-1 Signaling in the Brain the Culprit?
Endocrinology, October 1, 2008; 149(10): 4765 - 4767.
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