Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate
- Lebanese American University, Lebanon
- New York University Langone Medical Center, United States
- Burke Medical Research Institute, United States
- 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.
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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
- Joel K Elmquist, University of Texas Southwestern Medical Center, United States
Version history
- Received: February 8, 2016
- Accepted: May 24, 2016
- Accepted Manuscript published: June 2, 2016 (version 1)
- 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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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
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