Insulin regulates neurovascular coupling through astrocytes.

Autor:	Fernandez AM; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain.; Ciberned, Madrid, Spain., Martinez-Rachadell L; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain.; Ciberned, Madrid, Spain., Navarrete M; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain., Pose-Utrilla J; Ciberned, Madrid, Spain.; Laboratory of Novel Targets in Neurodegeneration and Neuroprotection. Instituto de Investigaciones Biomédicas 'Alberto Sols'. Consejo Superior de Investigaciones Cientificas- Universidad Autonoma de Madrid, Madrid, E 28029 Spain., Davila JC; Ciberned, Madrid, Spain.; Department of Cell Biology, Genetics and Physiology, Instituto de Investigación Biomédica de Malaga (IBIMA), Faculty of Sciences, University of Malaga, Malaga, E 29590 Spain., Pignatelli J; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain.; Ciberned, Madrid, Spain., Diaz-Pacheco S; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain., Guerra-Cantera S; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain.; Ciberned, Madrid, Spain., Viedma-Moreno E; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain.; Ciberned, Madrid, Spain., Palenzuela R; Dept Biochemistry and Molecular Biology. Faculty of Experimental Sciences, Universidad Francisco de Vitoria; Madrid, E 28223 Spain., Ruiz de Martin Esteban S; Dept Biochemistry and Molecular Biology. Faculty of Experimental Sciences, Universidad Francisco de Vitoria; Madrid, E 28223 Spain., Mostany R; Neuroscience Program, Tulane University School of Science and Engineering, New Orleans, LA 70118-5698., Garcia-Caceres C; Astrocyte Biology Unit. Institute for Diabetes and Obesity, Munich, D-85764 Germany., Tschöp M; Astrocyte Biology Unit. Institute for Diabetes and Obesity, Munich, D-85764 Germany., Iglesias T; Ciberned, Madrid, Spain.; Laboratory of Novel Targets in Neurodegeneration and Neuroprotection. Instituto de Investigaciones Biomédicas 'Alberto Sols'. Consejo Superior de Investigaciones Cientificas- Universidad Autonoma de Madrid, Madrid, E 28029 Spain., de Ceballos ML; Dept Systems and Functional Neuroscience. Cajal Institute, Consejo Superior de Investigaciones Cientificas, Madrid, E 28002 Spain., Gutierrez A; Ciberned, Madrid, Spain.; Department of Cell Biology, Genetics and Physiology, Instituto de Investigación Biomédica de Malaga (IBIMA), Faculty of Sciences, University of Malaga, Malaga, E 29590 Spain., Torres Aleman I; Ciberned, Madrid, Spain.; Laboratory of Neurobiology of Insulin Peptides. Achucarro Basque Center for Neuroscience, Leioa, E-48940 Spain.; Ikerbasque Basque Science Foundation, Bilbao, E 48011 Spain.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Jul 19; Vol. 119 (29), pp. e2204527119. Date of Electronic Publication: 2022 Jul 14.
DOI:	10.1073/pnas.2204527119
Abstrakt:	Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N -acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.
Databáze:	MEDLINE
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