Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure.
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.
Institut de Medecine Moleculaire de Rangueil, Toulouse III University, Centre Hospitalier Universitaire Rangueil, BP84225, 31432 Toulouse Cedex 4, France.
Claude
C
Knauf
Patrice D
PD
Cani
Afifa
A
Ait-Belgnaoui
Alexandre
A
Benani
Cédric
C
Dray
Cendrine
C
Cabou
André
A
Colom
Marc
M
Uldry
Sophie
S
Rastrelli
Eric
E
Sabatier
Natacha
N
Godet
Aurélie
A
Waget
Luc
L
Pénicaud
Philippe
P
Valet
Rémy
R
Burcelin
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology; D001933:Brain Stem / Q000502:physiology; D002245:Carbon Dioxide / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D006946:Hyperinsulinism / Q000188:drug therapy / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010807:Physical Endurance / Q000187:drug effects / Q000502:physiology; D052336:Proglucagon / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071246:Uncoupling Protein 2
D001786:Blood Glucose; D004041:Dietary Fats; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D002245:Carbon Dioxide; C083773:exendin (9-39); D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse