Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis
Carlos G. Ardanaz, Aida de la Cruz, Paras S. Minhas, Nira Hernández‐Martín, Miguel A. Pozo, M. Pilar Valdecantos, Ángela M. Valverde, Palmira Villa, Marcos Elizalde-Horcada, Elena Puerta, Marı́a J. Ramı́rez, Jorge E. Ortega, Ainhoa Urbiola, Cristina Ederra, Mikel Ariz, Carlos Ortíz-de-Solórzano, Joaquín Fernández‐Irigoyen, Enrique Santamaría, Gérard Karsenty, Jens C. Brüning, Maite Solas
Abstract
Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e., GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 reduction (GLUT1 ΔGFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Mechanistically, we observed that GLUT1-deficient astrocytes exhibited increased insulin receptor–dependent ATP release, and that both astrocyte insulin signaling and brain purinergic signaling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its depletion triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis, and cognitive function.