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

ABSTRACT: 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-?B, 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.

SUBMITTER: Marosi K

PROVIDER: S-EPMC5123937 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Marosi Krisztina K Kim Sang Woo SW Moehl Keelin K Scheibye-Knudsen Morten M Cheng Aiwu A Cutler Roy R Camandola Simonetta S Mattson Mark P MP

Journal of neurochemistry 20161114 5

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<sup>+</sup> /NADH ratio. We found that 3OHB metabolism increases mitochondrial respiratio ...[more]

PMID: 27739595

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Project description:BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT) 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or ?-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7), indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLC? signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during embryonic and neonatal development in contrast to adult tissue expressing only VGLUT1. These results suggest that BDNF regulates VGLUT expression during development and its effect on VGLUT1 may contribute to enhance glutamate release in LTP.

Dataset Information

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

Publications

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

Similar Datasets

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