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

During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3‐hydroxybutyrate (3 OHB ) occurs. Studies have shown that 3 OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms remain unclear. Neurons maintained in the presence of 3 OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD + / NADH ratio. We found that 3 OHB metabolism increases mitochondrial respiration which drives changes in expression of brain‐derived neurotrophic factor ( BDNF ) in cultured cerebral cortical neurons. The mechanism by which 3 OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF ‐κB, and activity of the histone acetyltransferase p300/ EP 300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3 OHB may mediate adaptive responses of neurons to fasting, exercise, and ketogenic diets.