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.DOI: http://dx.doi.org/10.7554/eLife.15092.001

Intermittent metabolic switching, neuroplasticity and brain health

“…BHB induces the expression of BDNF in cultured cerebral cortical neurons, an effect that occurs only when glucose levels are fairly low 62 . Running-wheel exercise increases circulating BHB levels in mice, and intraventricular infusion of BHB induces Bdnf gene transcription in hippocampal cells 55 . BHB may induce Bdnf gene transcription by inhibiting histone deacetylases (HDACs) that normally repress Bdnf expression 55,106 .…”

“…Running-wheel exercise increases circulating BHB levels in mice, and intraventricular infusion of BHB induces Bdnf gene transcription in hippocampal cells 55 . BHB may induce Bdnf gene transcription by inhibiting histone deacetylases (HDACs) that normally repress Bdnf expression 55,106 . Given that CR, fasting and exogenous ketone supplementation increase histone acetylation in peripheral mouse tissue and that exercise decreases histone deacetylation in the hippocampus, it is likely that the inhibitory effects of ketones on HDACs are amplified when exercise occurs in the fasted state 107 .…”

“…Insulin-like growth factor 1 (IGF1) signalling is also upregulated in response to IMS as demonstrated in studies of the effects of ketogenic diets, exercise and CR and/or IF on brain IGF1 signalling 51–53 . Two recent studies showed that BHB induces BDNF expression in hippocampal and cortical neurons in cell culture and in vivo 54,55 , suggesting that BHB is itself a signal that ‘alerts’ neurons in the brain that the metabolic switch has occurred.…”

“…PGC1α is also essential for the long-term maintenance of dendritic spines of hippocampal dentate granule neurons in adult mice 65 . Because BDNF expression is upreg-ulated in response to the G-to-K switch and BHB 54,55 , BDNF signalling may stimulate mitochondrial biogenesis to provide the increased numbers of mitochondria required to support the function of newly formed and potentiated synapses (FIG. 2).…”

“…Interestingly, selective ablation of the BDNF receptor TrkB in hippocampal neural stem cells abolishes the abilities of wheel running and anti-depressant drugs to ameliorate anxiety and depression in mice 165 . The recent finding that BHB induces BDNF expression in hippocampal and cortical neurons 54,55 suggests that ketones mediate the antidepressant effects of exercise and IF. Anxiolytic and antidepressant effects of IGF1 are suggested by data showing that peripheral administration of IGF1 exerts antidepressant actions, whereas peripheral IGF1-neutralizing antibodies attenuate the antidepressant effects of exercise in mice 166,167 .…”