title: Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.
abstract: We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Cristina
authors: C
authors: García-Cáceres
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Carmelo
authors: C
authors: Quarta
authors: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Luis
authors: L
authors: Varela
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Yuanqing
authors: Y
authors: Gao
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Tim
authors: T
authors: Gruber
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Beata
authors: B
authors: Legutko
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Martin
authors: M
authors: Jastroch
authors: Institute of Stem Cell Research Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Physiological Genomics, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany; 7SYNERGY, Excellence Cluster Systems Neurology, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany.
authors: Pia
authors: P
authors: Johansson
authors: Institute of Stem Cell Research Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Physiological Genomics, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany; 7SYNERGY, Excellence Cluster Systems Neurology, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany.
authors: Jovica
authors: J
authors: Ninkovic
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Chun-Xia
authors: CX
authors: Yi
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Ophelia
authors: O
authors: Le Thuc
authors: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Klara
authors: K
authors: Szigeti-Buck
authors: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors: Weikang
authors: W
authors: Cai
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Carola W
authors: CW
authors: Meyer
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors: Paul T
authors: PT
authors: Pfluger
authors: Institute Cajal, CSIC, 28002 Madrid, Spain.
authors: Ana M
authors: AM
authors: Fernandez
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, 75205 Paris, France.
authors: Serge
authors: S
authors: Luquet
authors: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2170 Galbraith Avenue, Cincinnati, OH 45237, USA.
authors: Stephen C
authors: SC
authors: Woods
authors: Institute Cajal, CSIC, 28002 Madrid, Spain.
authors: Ignacio
authors: I
authors: Torres-Alemán
authors: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors: C Ronald
authors: CR
authors: Kahn
authors: Institute of Stem Cell Research Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Physiological Genomics, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany; 7SYNERGY, Excellence Cluster Systems Neurology, Biomedical Center, Ludwigs-Maximilians-University, 80336 Munich, Germany.
authors: Magdalena
authors: M
authors: Götz
authors: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Tamas L
authors: TL
authors: Horvath
authors: Helmholtz Diabetes Center (HDC) & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany. Electronic address: tschoep@helmholtz-muenchen.de.
authors: Matthias H
authors: MH
authors: Tschöp
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D027322:Amino Acid Transport System X-AG; D005904:Glial Fibrillary Acidic Protein; D007328:Insulin; C528900:glial fibrillary astrocytic protein, mouse; D011333:Pro-Opiomelanocortin; D011972:Receptor, Insulin; D005947:Glucose
keywords: astrocytes; glucose uptake; hypothalamus; insulin receptor