1: Diabetes. 2008 Oct;57(10):2603-12. Epub 2008 Jun 2. Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing. Knauf C, Cani PD, Kim DH, Iglesias MA, Chabo C, Waget A, Colom A, Rastrelli S, Delzenne NM, Drucker DJ, Seeley RJ, Burcelin R. Institut de Medecine Moleculaire de Rangueil, Institut National de la Santé et de la Recherche Médicale U858, IFR31, Centre Hospitalier Universitaire Rangueil, Toulouse, France. 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. PMCID: PMC2551668 [Available on 10/01/09] PMID: 18519802 [PubMed - in process] Related Links Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. [Endocrinology. 1997] PMID:9322962 An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. [Gastroenterology. 2008] PMID:18313669 Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. [Gastroenterology. 2004] PMID:15300587 Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. [Diabetes. 2001] PMID:11473030 Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. [J Clin Invest. 2005] PMID:16322793