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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / metabolism
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Body Temperature Regulation / drug effects
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Body Temperature Regulation / physiology
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Brain Stem / physiology
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Carbon Dioxide / metabolism
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Diabetes Mellitus, Type 2 / drug therapy
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Diabetes Mellitus, Type 2 / metabolism*
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Dietary Fats / pharmacology*
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Energy Metabolism / drug effects
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Energy Metabolism / physiology
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Glucagon-Like Peptide 1 / metabolism*
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Glucose Intolerance / drug therapy
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Glucose Intolerance / metabolism
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Hyperinsulinism / drug therapy
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Hyperinsulinism / metabolism
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Insulin Resistance / physiology*
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Ion Channels / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mitochondrial Proteins / metabolism
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Motor Activity / drug effects
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Motor Activity / physiology
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Muscle, Skeletal / metabolism
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type III
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Oxygen Consumption / drug effects
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Oxygen Consumption / physiology
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Peptide Fragments / pharmacology
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Physical Endurance / drug effects
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Physical Endurance / physiology
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Proglucagon / genetics
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RNA, Messenger / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Uncoupling Protein 2
Substances
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Blood Glucose
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Dietary Fats
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Ion Channels
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Mitochondrial Proteins
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Peptide Fragments
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RNA, Messenger
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Ucp2 protein, mouse
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Uncoupling Protein 2
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Carbon Dioxide
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exendin (9-39)
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Proglucagon
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Glucagon-Like Peptide 1
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Nitric Oxide Synthase Type II
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Nitric Oxide Synthase Type III
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Nos3 protein, mouse