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.
Knauf
Claude
C
Institut de Medecine Moleculaire de Rangueil, Institut National de la Santé et de la Recherche Médicale U858, IFR31, Centre Hospitalier Universitaire Rangueil, Toulouse, France.
Cani
Patrice D
PD
Kim
Dong-Hoon
DH
Iglesias
Miguel A
MA
Chabo
Chantal
C
Waget
Aurélie
A
Colom
André
A
Rastrelli
Sophie
S
Delzenne
Nathalie M
NM
Drucker
Daniel J
DJ
Seeley
Randy J
RJ
Burcelin
Remy
R
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