1. Cell Biology

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
https://doi.org/10.7554/eLife.15092
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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

  • 56,254
    views
  • 4,797
    downloads
  • 473
    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

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    A syngeneic spontaneous zebrafish model of tp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapse in vivo

    Alex Weiss, Cassandra D'Amata ... Madeline N Hayes
    Research Article

    High-throughput vertebrate animal model systems for the study of patient-specific biology and new therapeutic approaches for aggressive brain tumors are currently lacking, and new approaches are urgently needed. Therefore, to build a patient-relevant in vivo model of human glioblastoma, we expressed common oncogenic variants including activated human EGFRvIII and PI3KCAH1047R under the control of the radial glial-specific promoter her4.1 in syngeneic tp53 loss-of-function mutant zebrafish. Robust tumor formation was observed prior to 45 days of life, and tumors had a gene expression signature similar to human glioblastoma of the mesenchymal subtype, with a strong inflammatory component. Within early stage tumor lesions, and in an in vivo and endogenous tumor microenvironment, we visualized infiltration of phagocytic cells, as well as internalization of tumor cells by mpeg1.1:EGFP+ microglia/macrophages, suggesting negative regulatory pressure by pro-inflammatory cell types on tumor growth at early stages of glioblastoma initiation. Furthermore, CRISPR/Cas9-mediated gene targeting of master inflammatory transcription factors irf7 or irf8 led to increased tumor formation in the primary context, while suppression of phagocyte activity led to enhanced tumor cell engraftment following transplantation into otherwise immune-competent zebrafish hosts. Altogether, we developed a genetically relevant model of aggressive human glioblastoma and harnessed the unique advantages of zebrafish including live imaging, high-throughput genetic and chemical manipulations to highlight important tumor-suppressive roles for the innate immune system on glioblastoma initiation, with important future opportunities for therapeutic discovery and optimizations.

    1. Cancer Biology
    2. Cell Biology

    Cancer: Modeling glioblastoma

    Ian Lorimer
    Insight

    Establishing a zebrafish model of a deadly type of brain tumor highlights the role of the immune system in the early stages of the disease.

    1. Cell Biology
    2. Neuroscience

    Presynaptic Rac1 in the hippocampus selectively regulates working memory

    Jaebin Kim, Edwin Bustamante ... Scott H Soderling
    Research Article

    One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear. Here, we show that spatial working memory in mice is selectively impaired following the expression of a genetically encoded Rac1 inhibitor at presynaptic terminals, while longer-term cognitive processes are affected by Rac1 inhibition at postsynaptic sites. To investigate the regulatory mechanisms of this presynaptic process, we leveraged new advances in mass spectrometry to identify the proteomic and post-translational landscape of presynaptic Rac1 signaling. We identified serine/threonine kinases and phosphorylated cytoskeletal signaling and synaptic vesicle proteins enriched with active Rac1. The phosphorylated sites in these proteins are at positions likely to have regulatory effects on synaptic vesicles. Consistent with this, we also report changes in the distribution and morphology of synaptic vesicles and in postsynaptic ultrastructure following presynaptic Rac1 inhibition. Overall, this study reveals a previously unrecognized presynaptic role of Rac1 signaling in cognitive processes and provides insights into its potential regulatory mechanisms.