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.

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.

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

  • 57,419
    views
  • 4,909
    downloads
  • 531
    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. Cell Biology
    Chengfang Pan, Ying Liu ... Changlong Hu
    Research Article

    Prostaglandin E2 (PGE2) is an endogenous inhibitor of glucose-stimulated insulin secretion (GSIS) and plays an important role in pancreatic β-cell dysfunction in type 2 diabetes mellitus (T2DM). This study aimed to explore the underlying mechanism by which PGE2 inhibits GSIS. Our results showed that PGE2 inhibited Kv2.2 channels via increasing PKA activity in HEK293T cells overexpressed with Kv2.2 channels. Point mutation analysis demonstrated that S448 residue was responsible for the PKA-dependent modulation of Kv2.2. Furthermore, the inhibitory effect of PGE2 on Kv2.2 was blocked by EP2/4 receptor antagonists, while mimicked by EP2/4 receptor agonists. The immune fluorescence results showed that EP1–4 receptors are expressed in both mouse and human β-cells. In INS-1(832/13) β-cells, PGE2 inhibited voltage-gated potassium currents and electrical activity through EP2/4 receptors and Kv2.2 channels. Knockdown of Kcnb2 reduced the action potential firing frequency and alleviated the inhibition of PGE2 on GSIS in INS-1(832/13) β-cells. PGE2 impaired glucose tolerance in wild-type mice but did not alter glucose tolerance in Kcnb2 knockout mice. Knockout of Kcnb2 reduced electrical activity, GSIS and abrogated the inhibition of PGE2 on GSIS in mouse islets. In conclusion, we have demonstrated that PGE2 inhibits GSIS in pancreatic β-cells through the EP2/4-Kv2.2 signaling pathway. The findings highlight the significant role of Kv2.2 channels in the regulation of β-cell repetitive firing and insulin secretion, and contribute to the understanding of the molecular basis of β-cell dysfunction in diabetes.

    1. Cell Biology
    Weihua Wang, Junqiao Xing ... Zhangfeng Hu
    Research Article

    Existence of cilia in the last eukaryotic common ancestor raises a fundamental question in biology: how the transcriptional regulation of ciliogenesis has evolved? One conceptual answer to this question is by an ancient transcription factor regulating ciliary gene expression in both uni- and multicellular organisms, but examples of such transcription factors in eukaryotes are lacking. Previously, we showed that an ancient transcription factor X chromosome-associated protein 5 (Xap5) is required for flagellar assembly in Chlamydomonas. Here, we show that Xap5 and Xap5-like (Xap5l) are two conserved pairs of antagonistic transcription regulators that control ciliary transcriptional programs during spermatogenesis. Male mice lacking either Xap5 or Xap5l display infertility, as a result of meiotic prophase arrest and sperm flagella malformation, respectively. Mechanistically, Xap5 positively regulates the ciliary gene expression by activating the key regulators including Foxj1 and Rfx families during the early stage of spermatogenesis. In contrast, Xap5l negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage. Our results provide new insights into the mechanisms by which temporal and spatial transcription regulators are coordinated to control ciliary transcriptional programs during spermatogenesis.