TY - JOUR
T1 - GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution
AU - Karaca, Melis
AU - Frigerio, Francesca
AU - Migrenne, Stephanie
AU - Martin-Levilain, Juliette
AU - Skytt, Dorte M
AU - Pajecka, Kamilla
AU - Martin-del-Rio, Rafael
AU - Gruetter, Rolf
AU - Tamarit-Rodriguez, Jorge
AU - Waagepetersen, Helle S
AU - Magnan, Christophe
AU - Maechler, Pierre
N1 - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2015/10/13
Y1 - 2015/10/13
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2015.09.003
DO - 10.1016/j.celrep.2015.09.003
M3 - Journal article
C2 - 26440896
SN - 2639-1856
VL - 13
SP - 365
EP - 375
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -