title: Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.
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.
authors.affiliation: Department of Natural Sciences, Lebanese American University, Byblos, Lebanon.
authors.forename: Sama F
authors.initials: SF
authors.lastname: Sleiman
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.|Department of Cell Biology, New York University Langone Medical Center, New York, United States.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, United States.|Department of Psychiatry, New York University Langone Medical Center, New York, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Henry
authors.affiliation: Department of Natural Sciences, Lebanese American University, Byblos, Lebanon.
authors.forename: Rami
authors.initials: R
authors.lastname: Al-Haddad
authors.affiliation: Department of Natural Sciences, Lebanese American University, Byblos, Lebanon.
authors.forename: Lauretta
authors.initials: L
authors.lastname: El Hayek
authors.affiliation: Department of Natural Sciences, Lebanese American University, Byblos, Lebanon.
authors.forename: Edwina
authors.initials: E
authors.lastname: Abou Haidar
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.|Department of Cell Biology, New York University Langone Medical Center, New York, United States.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, United States.|Department of Psychiatry, New York University Langone Medical Center, New York, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stringer
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.|Department of Cell Biology, New York University Langone Medical Center, New York, United States.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, United States.|Department of Psychiatry, New York University Langone Medical Center, New York, United States.
authors.forename: Devyani
authors.initials: D
authors.lastname: Ulja
authors.affiliation: Burke Medical Research Institute, White Plains, United States.|Brain Mind Research Institue, Weill Medical College of Cornell University, New York, United States.
authors.forename: Saravanan S
authors.initials: SS
authors.lastname: Karuppagounder
authors.affiliation: Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, United States.|Atlas Venture, Cambridge, United States.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.affiliation: Burke Medical Research Institute, White Plains, United States.|Brain Mind Research Institue, Weill Medical College of Cornell University, New York, United States.
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.|Department of Cell Biology, New York University Langone Medical Center, New York, United States.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, United States.|Department of Psychiatry, New York University Langone Medical Center, New York, United States.
authors.forename: Ipe
authors.initials: I
authors.lastname: Ninan
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.|Department of Cell Biology, New York University Langone Medical Center, New York, United States.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, United States.|Department of Psychiatry, New York University Langone Medical Center, New York, United States.
authors.forename: Moses V
authors.identifier: 0000-0002-6969-3744
authors.initials: MV
authors.lastname: Chao
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010805:Physical Conditioning, Animal; D020813:Receptor, trkB / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D020155:3-Hydroxybutyric Acid; D019208:Brain-Derived Neurotrophic Factor; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D006657:Histones; D018377:Neurotransmitter Agents; D020813:Receptor, trkB; D000099186:Histone Deacetylase 3; C533424:Hdac2 protein, mouse
keywords: HDAC inhibitors; bdnf; beta hydroxybutyrate; cell biology; epigenetics; mouse; physical exercise