Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis

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 paradoxic...

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Published in:Science advances 2024-10, Vol.10 (42), p.eadp1115
Main Authors: Ardanaz, Carlos G, de la Cruz, Aida, Minhas, Paras S, Hernández-Martín, Nira, Pozo, Miguel Ángel, Valdecantos, M Pilar, Valverde, Ángela M, Villa-Valverde, Palmira, Elizalde-Horcada, Marcos, Puerta, Elena, Ramírez, María J, Ortega, Jorge E, Urbiola, Ainhoa, Ederra, Cristina, Ariz, Mikel, Ortiz-de-Solórzano, Carlos, Fernández-Irigoyen, Joaquín, Santamaría, Enrique, Karsenty, Gerard, Brüning, Jens C, Solas, Maite
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Astrocytes - metabolism
Brain - metabolism
Energy Metabolism
Glucose - metabolism
Glucose Transporter Type 1 - genetics
Glucose Transporter Type 1 - metabolism
Homeostasis
Insulin - metabolism
Mice
Mice, Knockout
Obesity - metabolism
Receptor, Insulin - metabolism
Signal Transduction
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Summary: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 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adp1115