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Ketones are neurotrophic

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Elife. 2016 Jun 2;5. pii: e15092. doi: 10.7554/eLife.15092.

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

Sleiman SF(1), Henry J(2)(3)(4)(5), Al-Haddad R(1), El Hayek L(1), Abou Haidar
E(1), Stringer T(2)(3)(4)(5), Ulja D(2)(3)(4)(5), Karuppagounder SS(6)(7), Holson
EB(8)(9), Ratan RR(6)(7), Ninan I(2)(3)(4)(5), Chao MV(2)(3)(4)(5).

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: 10.7554/eLife.15092 
PMCID: PMC4915811
PMID: 27253067 


J Neurochem. 2016 Dec;139(5):769-781. doi: 10.1111/jnc.13868. Epub 2016 Nov 14.

3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in
cerebral cortical neurons.

Marosi K(1), Kim SW(1), Moehl K(1), Scheibye-Knudsen M(2), Cheng A(1), Cutler
R(1), Camandola S(1), Mattson MP(1)(3).

Author information: 
(1)Laboratory of Neurosciences, National Institute on Aging Intramural Research
Program, Baltimore, Maryland, USA.
(2)Center for Healthy Aging, Department of Cellular and Molecular Medicine,
University of Copenhagen, Copenhagen, Denmark.
(3)Department of Neuroscience, Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA.

During fasting and vigorous exercise, a shift of brain cell energy substrate
utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies
have shown that 3OHB can protect neurons against excitotoxicity and oxidative
stress, but the underlying mechanisms remain unclear. Neurons maintained in the
presence of 3OHB exhibited increased oxygen consumption and ATP production, and
an elevated NAD+ /NADH ratio. We found that 3OHB metabolism increases
mitochondrial respiration which drives changes in expression of brain-derived
neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism
by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen
species, activation of the transcription factor NF-κB, and activity of the
histone acetyltransferase p300/EP300. Because BDNF plays important roles in
synaptic plasticity and neuronal stress resistance, our findings suggest cellular
signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to
fasting, exercise, and ketogenic diets.

Published 2016. This article is a U.S. Government work and is in the public
domain in the USA.

DOI: 10.1111/jnc.13868 
PMCID: PMC5123937
PMID: 27739595 


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