The role of CNS GLP-1 receptors in enteric glucose sensing

Abstract

Objective: Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain that 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 the study was to determine in the brain the cells 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 GLP-1 receptor knockout mice, NPY and POMC-GFP expressing mice, and high-fat diet diabetic mice. We quantified the whole body glucose utilization rate, 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 following 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 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-1 receptor signaling and is impaired during diabetes.