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 paradoxically augmented in mice with astrocytic GLUT1 reduction (GLUT1<sup>ΔGFAP</sup> 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.
Authors
- Cristina Ederra (ORCID: https://orcid.org/0009-0003-9876-4657)
- Mikel Ariz (ORCID: https://orcid.org/0000-0002-7328-1582)
- Elena Puerta (ORCID: https://orcid.org/0000-0001-5695-5787)
- Carlos G. Ardanaz (ORCID: https://orcid.org/0000-0001-5328-2986)
- M. Pilar Valdecantos
- Angela Martinez Valverde (ORCID: https://orcid.org/0000-0003-1192-9045)
- Aida de la Cruz (ORCID: https://orcid.org/0000-0002-6039-8263)
- Marı́a J. Ramı́rez (ORCID: https://orcid.org/0000-0002-3488-9579)
- Jorge E. Ortega (ORCID: https://orcid.org/0000-0001-8188-874X)
- Paras S. Minhas (ORCID: https://orcid.org/0000-0002-7741-3327)
- Carlos Ortíz-de-Solórzano (ORCID: https://orcid.org/0000-0001-8720-0205)
- Marcos Elizalde-Horcada
- Ainhoa Urbiola
- Enrique Santamaría (ORCID: https://orcid.org/0000-0001-8046-8102)
- Joaquín Fernández‐Irigoyen (ORCID: https://orcid.org/0000-0001-5072-4099)
- Maite Solas (ORCID: https://orcid.org/0000-0001-7670-3237)
- Gérard Karsenty (ORCID: https://orcid.org/0000-0002-9253-7627)
- Nira Hernández‐Martín (ORCID: https://orcid.org/0009-0009-3933-1804)
- Palmira Villa (ORCID: https://orcid.org/0000-0001-9054-9176)
- Jens C. Brüning
- Miguel A. Pozo (ORCID: https://orcid.org/0000-0001-9303-0513)
Institutions
- Universidad Complutense de Madrid (ES)
- Memorial Sloan Kettering Cancer Center (US)
- University of the Basque Country (ES)
- Universidad Pública de Navarra (UPNA) (ES)
- Universidad Francisco de Vitoria (ES)
- BioCruces Health research Institute (ES)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES)
- Achucarro Basque Center for Neuroscience (ES)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Max Planck Institute for Metabolism Research (DE)
- Navarre Institute of Health Research (ES)
- Navarrabiomed (ES)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- German Center for Diabetes Research (DE)
- Universidad Autónoma de Madrid (ES)
- Columbia University (US)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1126/sciadv.adp1115
- Citations
- 23
- Primary Topic
- Metabolism, Diabetes, and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 5.38
Funders
- Universidad de Navarra