Neurons require glucose uptake and glycolysis in vivo

Summary: Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cy...

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Main Authors: Huihui Li, Caroline Guglielmetti, Yoshitaka J. Sei, Misha Zilberter, Lydia M. Le Page, Lauren Shields, Joyce Yang, Kevin Nguyen, Brice Tiret, Xiao Gao, Neal Bennett, Iris Lo, Talya L. Dayton, Martin Kampmann, Yadong Huang, Jeffrey C. Rathmell, Matthew Vander Heiden, Myriam M. Chaumeil, Ken Nakamura
Format: Article
Language:English
Published: Elsevier 2023-04-01
Series:Cell Reports
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124723003467
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author Huihui Li
Caroline Guglielmetti
Yoshitaka J. Sei
Misha Zilberter
Lydia M. Le Page
Lauren Shields
Joyce Yang
Kevin Nguyen
Brice Tiret
Xiao Gao
Neal Bennett
Iris Lo
Talya L. Dayton
Martin Kampmann
Yadong Huang
Jeffrey C. Rathmell
Matthew Vander Heiden
Myriam M. Chaumeil
Ken Nakamura
author_facet Huihui Li
Caroline Guglielmetti
Yoshitaka J. Sei
Misha Zilberter
Lydia M. Le Page
Lauren Shields
Joyce Yang
Kevin Nguyen
Brice Tiret
Xiao Gao
Neal Bennett
Iris Lo
Talya L. Dayton
Martin Kampmann
Yadong Huang
Jeffrey C. Rathmell
Matthew Vander Heiden
Myriam M. Chaumeil
Ken Nakamura
author_sort Huihui Li
collection DOAJ
description Summary: Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.
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spelling doaj.art-5e1e130f24524f59b205438e36d2ce002023-04-08T05:11:01ZengElsevierCell Reports2211-12472023-04-01424112335Neurons require glucose uptake and glycolysis in vivoHuihui Li0Caroline Guglielmetti1Yoshitaka J. Sei2Misha Zilberter3Lydia M. Le Page4Lauren Shields5Joyce Yang6Kevin Nguyen7Brice Tiret8Xiao Gao9Neal Bennett10Iris Lo11Talya L. Dayton12Martin Kampmann13Yadong Huang14Jeffrey C. Rathmell15Matthew Vander Heiden16Myriam M. Chaumeil17Ken Nakamura18Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USADepartment of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USAGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USAGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USADepartment of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USAGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USAGraduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USAGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USADepartment of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USADepartment of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA; UCSF/UCB Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA 94158, USAGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USAGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USAKoch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USAGraduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA; UCSF/UCB Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USAGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USAVanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USAKoch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USADepartment of Physical Therapy and Rehabilitation Science, San Francisco, CA 94158, USA; Department of Radiology and Biomedical Imaging, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; UCSF/UCB Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA 94158, USA; Corresponding authorGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding authorSummary: Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.http://www.sciencedirect.com/science/article/pii/S2211124723003467CP: Neuroscience
spellingShingle Huihui Li
Caroline Guglielmetti
Yoshitaka J. Sei
Misha Zilberter
Lydia M. Le Page
Lauren Shields
Joyce Yang
Kevin Nguyen
Brice Tiret
Xiao Gao
Neal Bennett
Iris Lo
Talya L. Dayton
Martin Kampmann
Yadong Huang
Jeffrey C. Rathmell
Matthew Vander Heiden
Myriam M. Chaumeil
Ken Nakamura
Neurons require glucose uptake and glycolysis in vivo
Cell Reports
CP: Neuroscience
title Neurons require glucose uptake and glycolysis in vivo
title_full Neurons require glucose uptake and glycolysis in vivo
title_fullStr Neurons require glucose uptake and glycolysis in vivo
title_full_unstemmed Neurons require glucose uptake and glycolysis in vivo
title_short Neurons require glucose uptake and glycolysis in vivo
title_sort neurons require glucose uptake and glycolysis in vivo
topic CP: Neuroscience
url http://www.sciencedirect.com/science/article/pii/S2211124723003467
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