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

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.

Reviewing Editor

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

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.

Version 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.

Metrics

  • 55,962
    views
  • 4,770
    downloads
  • 463
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2016)
Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate
eLife 5:e15092.
https://doi.org/10.7554/eLife.15092

Share this article

https://doi.org/10.7554/eLife.15092

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Christopher TA Lewis, Elise G Melhedegaard ... Julien Ochala
    Research Article

    Hibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators, Ictidomys tridecemlineatus and Eliomys quercinus and larger hibernators, Ursus arctos and Ursus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure in U. arctos and U. americanus during hibernation, whilst in I. tridecemlineatus and E. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20 °C). Upon repeating loaded Mant-ATP chase experiments at 8 °C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77–107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor in I. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.

    1. Cell Biology
    Jun Yang, Shitian Zou ... Xiaochun Bai
    Research Article

    Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.