Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing

C Knauf, PD Cani, DH Kim, MA Iglesias, C Chabo… - Diabetes, 2008 - Am Diabetes Assoc
C Knauf, PD Cani, DH Kim, MA Iglesias, C Chabo, A Waget, A Colom, S Rastrelli…
Diabetes, 2008Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc