1. Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure.
- Author
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Knauf C, Cani PD, Ait-Belgnaoui A, Benani A, Dray C, Cabou C, Colom A, Uldry M, Rastrelli S, Sabatier E, Godet N, Waget A, Pénicaud L, Valet P, and Burcelin R
- Subjects
- Animals, Blood Glucose metabolism, Body Temperature Regulation drug effects, Body Temperature Regulation physiology, Brain Stem physiology, Carbon Dioxide metabolism, Diabetes Mellitus, Type 2 drug therapy, Energy Metabolism drug effects, Energy Metabolism physiology, Glucose Intolerance drug therapy, Glucose Intolerance metabolism, Hyperinsulinism drug therapy, Hyperinsulinism metabolism, Ion Channels metabolism, Male, Mice, Mice, Inbred C57BL, Mitochondrial Proteins metabolism, Motor Activity drug effects, Motor Activity physiology, Muscle, Skeletal metabolism, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type III, Oxygen Consumption drug effects, Oxygen Consumption physiology, Peptide Fragments pharmacology, Physical Endurance drug effects, Physical Endurance physiology, Proglucagon genetics, RNA, Messenger metabolism, Signal Transduction drug effects, Uncoupling Protein 2, Diabetes Mellitus, Type 2 metabolism, Dietary Fats pharmacology, Glucagon-Like Peptide 1 metabolism, Insulin Resistance physiology, Signal Transduction physiology
- Abstract
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.
- Published
- 2008
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