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Role of Central Nervous System Glucagon-Like Peptide-1 Receptors in Enteric Glucose Sensing

¹ Institut de Medecine Moleculaire de Rangueil, Institut National de la Santé et de la Recherche Médicale U858, IFR31, Centre Hospitalier Universitaire Rangueil, Toulouse, France
² Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology, Université Catholique de Louvain, Brussels, Belgium
³ Department of Psychiatry, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio
⁴ Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Canada

Corresponding author: Remy Burcelin, remy.burcelin{at}inserm.fr

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.

RESEARCH DESIGN AND 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.

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				C. Cabou, G. Campistron, N. Marsollier, C. Leloup, C. Cruciani-Guglielmacci, L. Penicaud, D. J. Drucker, C. Magnan, and R. Burcelin Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity Diabetes, October 1, 2008; 57(10): 2577 - 2587. [Abstract] [Full Text] [PDF]