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Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate

  1. Sama F Sleiman
  2. Jeffrey Henry
  3. Rami Al-Haddad
  4. Lauretta El Hayek
  5. Edwina Abou Haidar
  6. Thomas Stringer
  7. Devyani Ulja
  8. Saravanan S Karuppagounder
  9. Edward B Holson
  10. Rajiv R Ratan
  11. Ipe Ninan
  12. Moses V Chao  Is a corresponding author
  1. Lebanese American University, Lebanon
  2. New York University Langone Medical Center, United States
  3. Burke Medical Research Institute, United States
  4. The Broad Institute of MIT and Harvard, United States
Research Article
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Cite this article as: eLife 2016;5:e15092 doi: 10.7554/eLife.15092

Abstract

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

Article and author information

Author details

  1. Sama F Sleiman

    Department of Natural Sciences, Lebanese American University, Byblos, Lebanon
    Competing interests
    No competing interests declared.
  2. Jeffrey Henry

    Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University Langone Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  3. Rami Al-Haddad

    Department of Natural Sciences, Lebanese American University, Byblos, Lebanon
    Competing interests
    No competing interests declared.
  4. Lauretta El Hayek

    Department of Natural Sciences, Lebanese American University, Byblos, Lebanon
    Competing interests
    No competing interests declared.
  5. Edwina Abou Haidar

    Department of Natural Sciences, Lebanese American University, Byblos, Lebanon
    Competing interests
    No competing interests declared.
  6. Thomas Stringer

    Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University Langone Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  7. Devyani Ulja

    Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University Langone Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  8. Saravanan S Karuppagounder

    Burke Medical Research Institute, White Plains, United States
    Competing interests
    No competing interests declared.
  9. Edward B Holson

    Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  10. Rajiv R Ratan

    Burke Medical Research Institute, White Plains, United States
    Competing interests
    No competing interests declared.
  11. Ipe Ninan

    Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University Langone Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  12. Moses V Chao

    Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University Langone Medical Center, New York, United States
    For correspondence
    moses.chao@med.nyu.edu
    Competing interests
    Moses V Chao, Reviewing editor, eLife.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the New York State Department of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of New York University (Approved Protocol (#140601) All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: February 8, 2016
  2. Accepted: May 24, 2016
  3. Accepted Manuscript published: June 2, 2016 (version 1)
  4. Version of Record published: June 21, 2016 (version 2)

Copyright

© 2016, Sleiman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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