title: GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution.
abstract: Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1(-/-) mice resulted in a central energy-deprivation state with increased ADP/ATP ratios and phospho-AMPK in the hypothalamus. This induced changes in the autonomous nervous system balance, with increased sympathetic activity promoting hepatic glucose production and mobilization of substrates reshaping peripheral energy stores. Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis.
authors.affiliation: Department of Cell Physiology and Metabolism, CMU, University of Geneva, rue Michel Servet 1, 1205 Geneva, Switzerland.
authors.forename: Melis
authors.initials: M
authors.lastname: Karaca
authors.affiliation: Department of Cell Physiology and Metabolism, CMU, University of Geneva, rue Michel Servet 1, 1205 Geneva, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Frigerio
authors.affiliation: CNRS, BFA, University Paris Diderot, 4 rue Marie Andrée Lagroua Weill-Halle, 75205 Paris Cedex 13, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Migrenne
authors.affiliation: Department of Cell Physiology and Metabolism, CMU, University of Geneva, rue Michel Servet 1, 1205 Geneva, Switzerland.
authors.forename: Juliette
authors.initials: J
authors.lastname: Martin-Levilain
authors.affiliation: Department of Drug Design and Pharmacotherapy, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.
authors.forename: Dorte M
authors.initials: DM
authors.lastname: Skytt
authors.affiliation: Department of Drug Design and Pharmacotherapy, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.
authors.forename: Kamilla
authors.initials: K
authors.lastname: Pajecka
authors.affiliation: Department of Biochemistry, Medical School, Complutense University, 28040 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Martin-del-Rio
authors.affiliation: LIFMET, CIBM, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Gruetter
authors.affiliation: Department of Biochemistry, Medical School, Complutense University, 28040 Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Tamarit-Rodriguez
authors.affiliation: Department of Drug Design and Pharmacotherapy, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
authors.affiliation: CNRS, BFA, University Paris Diderot, 4 rue Marie Andrée Lagroua Weill-Halle, 75205 Paris Cedex 13, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: Department of Cell Physiology and Metabolism, CMU, University of Geneva, rue Michel Servet 1, 1205 Geneva, Switzerland. Electronic address: pierre.maechler@unige.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D005969:Glutamate Dehydrogenase; D018698:Glutamic Acid / Q000378:metabolism*; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*
chemical_list: D017470:Receptors, Glutamate; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; C570817:GluD1 protein, mouse; D005969:Glutamate Dehydrogenase; D005947:Glucose