Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing.
OBJECTIVE
Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system.


METHODS
We selectively activated the axis in mice using a low-rate intragastric glucose infusion in wild-type and glucagon-like peptide-1 (GLP-1) receptor knockout mice, neuropeptide Y-and proopiomelanocortin-green fluorescent protein-expressing mice, and high-fat diet diabetic mice. We quantified the whole-body glucose utilization rate and the pattern of c-Fos positive in the brain.


RESULTS
Enteric glucose increased muscle glycogen synthesis by 30% and regulates c-Fos expression in the brainstem and the hypothalamus. Moreover, the synthesis of muscle glycogen was diminished after central infusion of the GLP-1 receptor (GLP-1Rc) antagonist Exendin 9-39 and abolished in GLP-1Rc knockout mice. Gut-glucose-sensitive c-Fos-positive cells of the arcuate nucleus colocalized with neuropeptide Y-positive neurons but not with proopiomelanocortin-positive neurons. Furthermore, high-fat feeding prevented the enteric activation of c-Fos expression.


CONCLUSIONS
We conclude that the gut-glucose sensor modulates peripheral glucose metabolism through a nutrient-sensitive mechanism, which requires brain GLP-1Rc signaling and is impaired during diabetes.
Institut de Medecine Moleculaire de Rangueil, Institut National de la Santé et de la Recherche Médicale U858, IFR31, Centre Hospitalier Universitaire Rangueil, Toulouse, France.
Claude
C
Knauf
Patrice D
PD
Cani
Dong-Hoon
DH
Kim
Miguel A
MA
Iglesias
Chantal
C
Chabo
Aurélie
A
Waget
André
A
Colom
Sophie
S
Rastrelli
Nathalie M
NM
Delzenne
Daniel J
DJ
Drucker
Randy J
RJ
Seeley
Remy
R
Burcelin
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism / Q000502:physiology*
D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D016760:Proto-Oncogene Proteins c-fos; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D006003:Glycogen; D005947:Glucose