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

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          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.

          DOI: http://dx.doi.org/10.7554/eLife.15092.001

          eLife digest

          Exercise is not only good for our physical health but it benefits our mental health and abilities too. Physical exercise can affect how much of certain proteins are made in the brain. In particular, the levels of a protein called brain derived neurotrophic factor (or BDNF for short) increase after exercise. BDNF has already been shown to enhance mental abilities at the same time as acting against anxiety and depression in mice, and might act in similar way in humans. Nevertheless, it is currently not clear how exercise increases the production of BDNF by cells in the brain.

          Sleiman et al. have now investigated this question by comparing mice that were allowed to use a running wheel for 30 days with control mice that did not exercise. The comparison showed that the exercising mice had higher levels of BDNF in their brains than the control mice, which confirms the results of previous studies. Next, biochemical experiments showed that this change occurred when enzymes known as histone deacetylases stopped inhibiting the production of BDNF. Therefore Sleiman et al. hypothesised that exercise might produce a chemical that itself inhibits the histone deacetylases.

          Indeed, the exercising mice produced more of a molecule called β-hydroxybutyrate in their livers, which travels through the blood into the brain where it could inhibit histone deacetylases. Further experiments showed that injecting β-hydroxybutyrate directly into the brains of mice led to increase in BDNF.

          These new findings reveal with molecular detail one way in which exercise can affect the expression of proteins in the brain. This new understanding may provide ideas for new therapies to treat psychiatric diseases, such as depression, and neurodegenerative disorders, such as Alzheimer’s disease.

          DOI: http://dx.doi.org/10.7554/eLife.15092.002

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          Most cited references39

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          A neurotrophic model for stress-related mood disorders.

          There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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            Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway.

            Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice. Neuronal Fndc5 gene expression is regulated by PGC-1α, and Pgc1a(-/-) mice show reduced Fndc5 expression in the brain. Forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, whereas RNAi-mediated knockdown of FNDC5 reduces Bdnf. Importantly, peripheral delivery of FNDC5 to the liver via adenoviral vectors, resulting in elevated blood irisin, induces expression of Bdnf and other neuroprotective genes in the hippocampus. Taken together, our findings link endurance exercise and the important metabolic mediators, PGC-1α and FNDC5, with BDNF expression in the brain. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Exercise and brain neurotrophins.

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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                02 June 2016
                2016
                : 5
                : e15092
                Affiliations
                [1 ]deptDepartment of Natural Sciences , Lebanese American University , Byblos, Lebanon
                [2 ]deptSkirball Institute of Biomolecular Medicine , New York University Langone Medical Center , New York, United States
                [3 ]deptDepartment of Cell Biology , New York University Langone Medical Center , New York, United States
                [4 ]deptDepartment of Neuroscience and Physiology , New York University Langone Medical Center , New York, United States
                [5 ]deptDepartment of Psychiatry , New York University Langone Medical Center , New York, United States
                [6 ]Burke Medical Research Institute , White Plains, United States
                [7 ]deptBrain Mind Research Institue , Weill Medical College of Cornell University , New York, United States
                [8 ]deptStanley Center for Psychiatric Research , The Broad Institute of MIT and Harvard , Cambridge, United States
                [9 ]Atlas Venture , Cambridge, United States
                [10]University of Texas Southwestern Medical Center , United States
                [11]University of Texas Southwestern Medical Center , United States
                Author notes
                Author information
                http://orcid.org/0000-0002-6969-3744
                Article
                15092
                10.7554/eLife.15092
                4915811
                27253067
                2905714c-77d6-4dac-888d-133e8c3078e3
                © 2016, Sleiman et al

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

                History
                : 08 February 2016
                : 24 May 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100005993, National Council for Scientific Research;
                Award ID: #699
                Award Recipient :
                Funded by: Lebanese American University;
                Award ID: SRDC seed grant
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HD076914
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NS21072
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AG025970
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Cell Biology
                Research Article
                Custom metadata
                2.5
                A potential link between metabolic changes resulting from exercise and gene expression in the brain has been revealed.

                Life sciences
                physical exercise,bdnf,beta hydroxybutyrate,hdac inhibitors,epigenetics,mouse
                Life sciences
                physical exercise, bdnf, beta hydroxybutyrate, hdac inhibitors, epigenetics, mouse

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