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.
Knauf
Claude
C
Institut de Medecine Moleculaire de Rangueil, Toulouse III University, Centre Hospitalier Universitaire Rangueil, BP84225, 31432 Toulouse Cedex 4, France.
Cani
Patrice D
PD
Ait-Belgnaoui
Afifa
A
Benani
Alexandre
A
Dray
Cédric
C
Cabou
Cendrine
C
Colom
André
A
Uldry
Marc
M
Rastrelli
Sophie
S
Sabatier
Eric
E
Godet
Natacha
N
Waget
Aurélie
A
Pénicaud
Luc
L
Valet
Philippe
P
Burcelin
Rémy
R
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