Brain glucose supply is regulated by the glucose transporter GLUT1, which is highly expressed in astrocytes. While vascular GLUT1 ablation leads to brain hypometabolism and cognitive impairment, this approach cannot differentiate between the effects of glucose insufficiency and those arising from vascular breakdown. To address this question, we investigated the role of astrocytic GLUT1 in glucose metabolism and cognition. In vitro studies using an extracellular flux analyzer (Seahorse) revealed that GLUT1-ablated astrocytes exhibited reduced glucose uptake and glycolysis but maintained ATP production. In vivo, astrocyte-specific GLUT1 deletion (GLUT1ΔGFAP), achieved through tamoxifen-inducible Cre/LoxP strategies, led to increased CNS glucose utilization and an improved metabolic profile. GLUT1ΔGFAP mice demonstrated enhanced ability to suppress hyperphagia and restore systemic glucose homeostasis after hyperglycemia. Notably, these mice performed memory tasks efficiently, suggesting preserved cognitive function. Further analysis showed that GLUT1-ablated astrocytes displayed upregulated insulin receptor (IR) expression and increased insulin-stimulated ATP release. Blocking brain purinergic signaling negated the metabolic and cognitive benefits observed in GLUT1ΔGFAP mice, while simultaneous ablation of GLUT1 and IR in astrocytes produced similar effects, which were reversed by brain purinergic stimulation. These findings indicate that astrocytic GLUT1 ablation shifts brain and systemic metabolism toward a more efficient glucose-handling phenotype and fosters memory resilience, requiring enhanced IR-dependent ATP release from astrocytes for these beneficial effects.

More information:

• https://portalcientifico.unav.edu/investigadores/327404/detalle