Astrocytic GLUT1 ablation improves systemic glucose metabolism and promotes cognition

Abstract

AbstractBackgroundGlucose supply from the blood to the brain is controlled by the glucose transporter GLUT1, highly expressed in astrocytes, which coordinate brain glucose supply, metabolization and storage. Ablating GLUT1 at the blood‐brain barrier (BBB) endothelial cells leads to BBB breakdown, brain glucose hypometabolism and impaired cognition, but this approach cannot discriminate between insufficient glucose supply and BBB breakdown‐derived effects. Such question is the focus of the present work, which aims to elucidate the relevance of astrocytic GLUT1 to cellular, brain and systemic glucose metabolism, and to cognition.MethodsTo address these questions, GLUT1 was ablated from primary astrocytes. Cellular metabolism was examined using an extracellular flux analyzer (Seahorse). In vivo, astrocytic GLUT1 was ablated using a tamoxifen‐inducible Cre/LoxP approach (GLUT1ΔGFAP mice). 18F‐FDG PET, glucose and insulin tolerance and insulin secretion and fasting‐induced hyperphagia were characterized. BBB integrity was examined by vessel immunostaining and capillary‐depleted brain analysis. Recognition and spatial memory were assessed using Novel Object Recognition and Morris Water Maze tasks. To address the implication of purinergic signaling in those effects, a purinergic receptor antagonist (PPADS) was intracerebroventricularly administered before each behavioral test.ResultsGLUT1‐ablated astrocytes showed reduced glucose uptake and glycolysis, although preserving total ATP production. Unexpectedly, postnatal astrocytic GLUT1 deletion increased CNS glucose utilization. GLUT1ΔGFAP mice showed an improved metabolic status from which obese animals especially benefited. Specifically, GLUT1ΔGFAP mice were more efficient at suppressing hyperphagia and readjusting systemic glucose levels after hyperglycemia, exhibiting marked increase in insulin secretion. These effects were coupled with enhanced BAT activity, and reduced BAT adiposity. In parallel with this improved systemic homeostasis, GLUT1ΔGFAP mice performed both recognition and spatial memory tasks properly, even outperforming control mice. Noteworthy, those effects could be due to higher astrocytic ATP release. Indeed, central administration of PPADS could reverse improvements in metabolic and cognitive behaviors in mice with astrocyte GLUT1 knockout.ConclusionOverall, this study demonstrates that astrocytic GLUT1 ablation impairs astrocytic glucose availability but enhances brain glucose utilization, reprograms systemic glucose metabolism towards a more efficient glucose‐handling phenotype and promotes cognitive abilities, which could be a key factor in neurodegenerative diseases such as Alzheimer’s disease.