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Brain Glucagon-Like Peptide 1 Signaling Controls the Onset of High-Fat Diet-Induced Insulin Resistance and Reduces Energy Expenditure

Institut de Medecine Moleculaire de Rangueil (I2MR) (C.K., P.D.C., C.D.,C.C., A.C., S.R., E.S., N.G., A.W., P.V., R.B.), Institut National de la Santé et de la Recherche Médicale Unité 858, Institut Fédératif de Recherche 31, Toulouse III University, Centre Hospitalier Universitaire Rangueil, 31432 Toulouse, France; Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology (P.D.C.), Université Catholique de Louvain, 1200 Brussels, Belgium; Neuro-Gastroenterology and Nutrition Unit (A.A.-B.), Unité Mixte de Recherche 1054 Institut National de la Recherche Agronomique/ESAP, 31931 Toulouse, France; Laboratoire Métabolisme Plasticité Mitochondrie (A.B., L.P.), Toulouse III University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5241, 31432 Toulouse, France; and Dana-Farber Cancer Institute and Department of Cell Biology (M.U.), Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Institut de Medecine Moleculaire de Rangueil (I2MR), Institut National de la Santé et de la Recherche Médicale Unité 858, Institut Fédératif de Recherche 31, Centre Hospitalier Universitaire Rangueil, BP84225, 31432 Toulouse Cedex 4, France. E-mail: remy.burcelin{at}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 1-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 exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.

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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. [Full Text] [PDF]