3-Hydroxybutyrate Regulates Energy Metabolism and Induces BDNF Expression in Cerebral Cortical Neurons

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

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-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.

Keywords: bdnf; ketone; mitochondria; nf-kb; p300.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology*
  • Animals
  • Brain-Derived Neurotrophic Factor / biosynthesis*
  • Brain-Derived Neurotrophic Factor / genetics
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Brain-Derived Neurotrophic Factor
  • 3-Hydroxybutyric Acid