BDNF-3-hydroxybuytrate-regulation-Seminal-2016

3-hydroxybutyrate (3OHB) increases basal oxygen consumption and ATP production without altering glycolytic rate. (a) 3OHB (1 mM) elevates the basal oxygen consumption rate (OCR) in primary cortical neurons in the presence and absence of 1 mM glucose (**p < 0.01). (b) The extracellular acidification rates (ECAR) were not altered by 1 mM 3OHB. (c) Acute, 1 h incubation with 1 mM 3OHB increases cellular ATP content (*p < 0.05).

3OHB increases metabolic rate by increasing functional changes in the mitochondria

To further examine the effect of 3OHB on neuronal energy metabolism, we measured oxygen consumption in cortical neurons treated with 3OHB for 24 h. After the pre-incubation in the treatment conditions, the metabolic assays were performed in serum-free unbuffered XF assay medium which contained equal amounts of energy substrates in each condition (5 mM glucose, 1 mM pyruvate, and 2 mM glutamax). The basal OCR normalized to neuronal numbers was elevated in the 3OHB-treated neurons (Fig. 2a and b). The ATP production was estimated from the OCR rates following the 1 μM oligomycin treatment. ATP production was higher in the 3OHB-treated neurons, which was confirmed by the direct measurement of cellular ATP content (Fig. 2c). The carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (2.5 mM)-stimulated maximal OCR was significantly elevated with 3OHB treatment showing an increase in mitochondrial oxidative capacity (Fig. 2b). The stimulation of maximal respiration by 3OHB was absent in high-glucose conditions (Fig. S1). The NAD+/NADH ratio was significantly increased in 3OHB-treated neurons (Fig. 2d), suggesting enhanced mitochondrial electron transport chain (ETC) activity. Next, we investigated whether the enhanced metabolic rate of 3OHB-treated neurons is related to increased numbers of mitochondria or altered expression of the ETC proteins. We found that the total mtDNA content and the mRNA levels of transcription factors that regulate mitochondrial biogenesis remained unchanged after 3OHB treatment for 24 h (Fig. 2e and f), indicating that 3OHB treatment did not affect the number of mitochondria/neuron. 3OHB-treated neurons exhibited an increase in the level of the mitochondrial complex I protein NDUFB8, but not three other mitochondrial complex proteins, UQCRC2, MTCO1, and succinate dehydrogenase (Fig. 2g), further supporting no effect of 3OHB on mitochondrial numbers. NDUFB8 is an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). The increase in levels of NDUFB8 in response to 3OHB may therefore lead to a higher NAD+ turnover rate (Fig. 2d) and an increase in ETC-mediated cellular respiration (Fig. 2b).

Figure 2

3-hydroxybutyrate (3OHB) stimulates mitochondrial respiration. The neurons were pre-treated with control medium containing 1 mM glucose (CTRL), or medium containing 8 mM 3OHB and 1 mM glucose for 24 h, and then incubated with unbuffered Seahorse XF medium for 1 h. (a) Key parameters of mitochondrial function were determined by measuring the oxygen consumption rate (OCR) of the neurons in the presence of modulators of respiration that target components of the electron transport chain. The compounds [oligomycin, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), and a mix of rotenone and antimycin A] were serially applied. The neurons and the recorded OCRs were used to quantify relative levels of ATP production and maximal respiration, respectively. Spare respiratory capacity was calculated using these parameters and basal respiration. Basal and FCCP-induced oxygen consumption rates (OCR) were elevated in primary cortical neurons treated with 8 mM 3OHB for 24 h compared to control cultures (CTRL). Representative graph shows the basal oxygen consumption rates (OCR) and the OCR values after oligomycin (1 μM), FCCP (1 μM), and rotenone plus antimycin A (0.5 μM) treatments measured using a Seahorse XF-96 instrument. p < 0.05 versus CTRL. (b) Values for basal OCR, maximal OCR, spare respiratory capacity (RC), and ATP production in cortical neurons that had been exposed for 24 h to vehicle (CTRL) or 8 mM 3OHB (n = 5 separate cultures). p < 0.05, p < 0.01, p < 0.001 versus CTRL. (c and d) Cortical neurons exhibited higher ATP levels (c) and NAD+/NADH ratio (d) after incubation with 8 mM 3OHB for 6 h compared to CTRL (n = 3 separate cultures). p < 0.05. (e) Results of quantitative polymerase chain reaction (PCR) analysis reveal that 8 mM 3OHB treatment does not affect the expression of genes involved in the regulation of mitochondrial biogenesis (n = 3 separate cultures). (f) Results of quantitative PCR analysis show that the mitochondrial DNA copy number is not affected by 3OHB (24 h treatment with 8 mM 3OHB) (n = 3 separate cultures). Mitochondrial DNA copy number was quantified as described in the Methods section. (g) Immunoblots showing relative levels of the indicated mitochondrial proteins in cortical neurons that were treated with vehicle (CTRL) or 8 mM 3OHB for 24 h.*p < 0.05, **p < 0.01.

3OHB increases Bdnf gene and protein expression

Primary neuronal cultures are typically maintained in medium containing a supraphysiological concentration of glucose (10–25 mM), whereas levels of extracellular glucose in the brain in vivo normally ranges from 0.2 to 2.5 mM in accord with changes in plasma glucose levels from hypoglycemia to hyperglycemic conditions (Silver and Erecinska 1994). We found that when cortical and hippocampal neurons were incubated in medium containing 1 mM glucose and treated for 24 h with 0.1–8 mM 3OHB, a concentration range that includes 3OHB concentrations ranging from those occurring during non-fasting conditions (0.1 mM) to a concentration achieved during extended fasting (8 mM) (Owen et al. 1967), Bdnf mRNA levels were significantly increased by approximately 3-fold within 6 h (Fig. 3a and b, and Fig. S2). In contrast, Bdnf expression was unaffected by 3OHB in cortical neurons incubated in medium containing a high-glucose concentration (10 mM). Similarly, there was a significant increase in the BDNF protein levels in the 3OHB-treated neurons incubated in medium containing 1 mM glucose, but not in those incubated in medium containing 10 mM glucose (Fig. 3b). There were no significant differences in the Bdnf gene expression in neurons incubated in low- compared to high-glucose conditions. (Fig. 3a and b). In a concentration–response study, we found that when cortical neurons were incubated in medium containing 1 mM glucose and treated for 24 h with 0.1–8 mM 3OHB, low concentrations of 3OHB (0.1 and 0.5 mM) had no significant effect on Bdnf mRNA levels, whereas 1 mM 3OHB significantly increased Bdnf mRNA levels (Fig. 3c). Previous studies have shown that, similar to butyrate, 3OHB is an endogenous and specific inhibitor of class I histone deacetylases (Shimazu et al. 2013). We investigated whether sodium–butyrate (Na-butyrate) can similarly regulate the expression of Bdnf. No induction of Bdnf by Na-butyrate was found (Fig. 3d), indicating that changes in Bdnf expression are not driven by the HDAC1 inhibitory properties of 3OHB.

Figure 3

3-hydroxybutyrate (3OHB) treatment increases brain-derived neurotrophic factor (BDNF) expression in cerebral cortical neurons. Cortical neurons were incubated in medium containing either a low (1 mM) or high (10 mM) concentration of glucose (GL) and were then exposed to 8 mM 3OHB or vehicle control (CTRL). Neurons were then harvested after either 6 h of 3OHB treatment for measurement of Bdnf mRNA levels (a) or 24 h for measurement of BDNF protein levels (b). Values are the mean and SEM of determinations made in five separate experiments. **p < 0.01, ***p < 0.001. (c) Bdnf gene expression levels were increased by 3OHB in primary cortical neurons in a concentration-dependent manner in 1 mM glucose condition. ***p < 0.001. (d) No induction of Bdnf gene by Na-butyrate (8 mM) was detected in 1 mM glucose condition.*p < 0.05.

The monocarboxylic acid transporter 2 mediates the uptake of 3OHB into neurons (Martin et al. 2006; Chiry et al. 2008). We found that mct2 mRNA levels were increased significantly in response to 3OHB (Fig. 4a). Pre-incubation with an inhibitor of the monocarboxylate transporters [1 μM AR-C155858 (AR-C)] abolished the enhancement in Bdnf mRNA levels by 3OHB (Fig. 4b), consistent with a requirement for cellular uptake of 3OHB in the mechanism by which 3OHB induces BDNF expression.

Figure 4

3-hydroxybutyrate (3OHB) treatment increases brain-derived neurotrophic factor (BDNF) expression in cerebral cortical neurons in a MCT2-dependent manner. (a) Cortical neurons were incubated in medium containing 1 mM glucose and were then exposed to 8 mM 3OHB for 6 h. Levels of mct2 mRNA were quantified (n = 5 separate cultures). ***p < 0.001. (b) Cortical neurons (in medium containing 1 mM glucose) were pre-incubated with or without the MCT2 inhibitor AR-C155858 (1 μM) for 1 h. The neurons were then treated with 8 mM 3OHB or vehicle control for 6 h and were then processed for measurement of Bdnf mRNA levels (n = 4 separate cultures). *p < 0.05.

NF-κB mediates 3OHB-induced Bdnf gene transcription

The rat Bdnf gene was reported to have four different promoters that regulate expression of distinct exons (Timmusk et al. 1993) that have been shown to be responsive to various stimuli including electrical activity, exercise, stress, and calcium influx (Shieh and Ghosh 1999; Sakata et al. 2010). To determine if and how 3OHB induces Bdnf gene expression, we transfected HEK293 cells with the luciferase gene driven by Bdnf promoter I, II, III, or IV. We found that 3OHB induces expression from Bdnf promoter IV, but not from promoters I, II, or III (Fig. S3). There was a slight increase in luciferase activity of promoter I as well so it is likely that the promoter I might also contribute to the effect of 3OHB on Bdnf gene expression. Two transcription factors that have been shown to induce Bdnf expression are cAMP response element-binding protein (CREB) and nuclear factor-κB (NF-κB) (Tao et al. 1998; Marini et al. 2004). We tested the phosphorylation of CREB and the nuclear translocation of NF-κB in response to 3OHB treatment. When neurons were treated with 3OHB for 6 h there was an increased amount of the NF-κB subunit p65 in the nucleus compared to vehicle-treated neurons (Fig. 5a). Treatment of neurons with the NF-κB inhibitor SN-50 (10 μM) completely blocked the ability of 3OHB to increase the level of nuclear p65 (Fig. 5a). Inhibition of NF-κB using SN-50 significantly suppressed 3OHB-induced Bdnf gene expression (Fig. 5b).

Figure 5

Evidence for the involvement of NF-κB and p300 in 3-hydroxybutyrate (3OHB)-induced Bdnf gene transcription. (a) Cortical neurons were pre-treated for 1 h without or with the NF-κB inhibitor SN50, were then treated with vehicle (CTRL) or 8 mM 3OHB for 6 h, and proteins in nuclei were isolated from the neurons and were subjected to immunoblot analysis with antibodies against the p65 subunit of NF-κB or the nuclear lamin A/B proteins. (b) NF-κB inhibition using 10 μM SN-50 suppressed the induction of Bdnf mRNA expression by 8 mM 3OHB in primary cortical neurons (n = 3 separate cultures). *p < 0.05. (c) Global histone acetyltransferase activity (HAT) was measured in primary cortical neurons at the indicated time points after exposure to vehicle (CTRL) or 8 mM 3OHB (n = 3 separate cultures). *p < 0.05. (d) Cortical neurons were exposed to vehicle (CTRL) or 8 mM 3OHB for 6 h and then the extracts were subjected to immunoprecipitation with an antibody against the p65 NF-κB protein and blotted with p300 antibody. Total NF-κB levels were used as the loading control. (e) Chromatin immunoprecipitation performed on cortical neurons that had been exposed to vehicle (CTRL) or 8 mM 3OHB for 6 h. Bdnf promoter targets (I, II, III, and IV) were evaluated by quantitative polymerase chain reaction (PCR). Quantification of immunoprecipitated material relative to its input level is represented as the fold induction (n = 3 separate cultures). *p < 0.05. Graph B shows that inhibition of p300 blocks the effect of 3OHB on Bdnf expression. Cortical neurons were pre-incubated with or without C646 (2.5 μM), a specific inhibitor of p300, for 1 h and the neurons were then treated with 3OHB or vehicle (CTRL) for 6 h (n = 3 separate cultures), *p < 0.05, **p < 0.01.

p300 interacts with NF-κB to regulate bdnf expression

It was reported that 3OHB can inhibit histone deacetylases (Shimazu et al. 2013) which might alter the dynamic balance between histone acetylation and deacetylation toward acetylation. Because histone acetylation can regulate gene transcription, we evaluated global HAT activity in nuclear extracts from primary neurons that had been exposed to 3OHB for 1 h. Compared to neurons in control cultures, neurons exposed to 3OHB exhibited significantly elevated nuclear HAT activity (Fig. 5c). p300 is a histone acetyltransferase and transcriptional co-activator that can interact with NF-κB to promote neuronal survival (Culmsee et al. 2003; Greene and Chen 2004). A co-immunoprecipitation assay revealed the binding of p300 to p65 in neurons treated with 3OHB for 6 h (Fig. 5d). We next tested the binding of p300 at promoters I–IV of the Bdnf gene. 3OHB significantly enhanced the recruitment of p 300 to the Bdnf promoter IV sequence (Fig. 5e). We then used a specific inhibitor of p300 (C646, 2.5 μM) to demonstrate a requirement for p300 in the stimulation of Bdnf gene expression by 3OHB (Fig 5b).

3OHB enhances mitochondrial oxidative metabolism which plays a role in the regulation of Bdnf gene expression

We next investigated the possible mechanism by which 3OHB triggers NF-κB activation and Bdnf gene transcription. Because metabolism of non-glycolytic substrates is accompanied by elevated levels of mitochondrial ROS (Forsberg et al. 1998), and because NF-κB and p300 are known to be redox-sensitive transcription regulators (Li et al. 1999; Dansen et al. 2009; Chen et al. 2011), we hypothesized that 3OHB-induced Bdnf gene transcription is mediated by mitochondrial ROS production. We found that exposure of cortical neurons to 3OHB resulted in an increase in ROS levels that was evident within 6 h (Fig. 6a and b). Consistent with an adaptive redox response to 3OHB, levels of the antioxidant enzyme SOD2 were elevated in 3OHB-treated neurons (Fig. 6c). Next, we determined whether the suppression of ROS production can affect 3OHB-induced Bdnf expression. We incubated cells with or without 3OHB and an antioxidant for 6 h and then measured Bdnf promoter IV activity. The antioxidants included the glutathione precursor N-acetylcysteine (10 μM) and the superoxide scavenger mitoTempo (5 μM); and cyclosporin A (0.5 μM) that prevents the opening of the mitochondria permeability transition pore in response to toxic insults. The antioxidants prevented the induction of Bdnf gene (Fig. 6d), although cyclosporin A did not have similar effect indicating that 3OHB does not cause alteration in the mitochondria permeability transition pore.

BDNF mediates the excitoprotective effect of 3OHB

Next, we investigated the functional role of the induction of BDNF by 3OHB. Neurons were pre-incubated with or without 3OHB for 6 h in the presence or absence of TrkB inhibitor ANA-12 (2 μM). 3OHB treatment slightly increased the survival of the neurons in the presence of kainic acid (Fig. S4). Although there was no difference in the neuronal survival between the groups when the TrkB receptor was blocked indicating that BDNF plays a role in the neuroprotective effect of 3OHB.

Exercise decreases plasma glucose levels, increases 3OHB levels, and induces BDNF in the brain

Aerobic exercise has been known to enhance brain BDNF levels. We investigated whether exercise induces changes in the concentration of the circulating energy sources for the neurons that might be associated with BDNF production in the brain. We tested the levels of the main energy sources, glucose, and 3OHB levels in the sedentary mice and in the mice subjected to 6 weeks of voluntary exercise. We also measured the BDNF levels in the hippocampus. We found that exercise decreased basal glucose levels and increased the 3OHB levels in the plasma (Fig. 7a and b). Hippocampal BDNF levels were also induced by aerobic exercise (Fig. 7c), which corresponds to previous data. In addition, we found a correlation between the circulating levels of 3OHB and the hippocampal BDNF levels, suggesting that 3OHB might regulate BDNF levels in vivo (Fig. S5).

Discussion

Our findings suggest that 3OHB induces expression of the Bdnf gene and increases BDNF protein levels in cerebral cortical neurons via activation of the Bdnf gene promoter IV by a mechanism involving the transcription factor NF-κB and the histone acetyltransferase p300. Inhibition of monocarboxylic acid transporter 2 prevented 3OHB-induced Bdnf expression indicating a requirement for cellular uptake of 3OHB for stimulation of Bdnf expression. Cultured primary neurons are typically maintained in media containing concentrations of glucose (10–25 mM) that would be considered pathologically hyperglycemic (i.e., diabetic) in vivo (e.g., Brewer et al. 1993). We found that whereas 3OHB stimulated Bdnf expression in neurons maintained in a relatively low concentration of glucose (1 mM), it did not increase Bdnf expression in neurons maintained in a high concentration of glucose (10 mM). During prolonged fasting, plasma glucose concentrations are maintained low (3–5 mM) while 3OHB concentrations are elevated greatly (5–10 mM). However, under the latter conditions the extracellular glucose concentration in the brain is believed to be considerably lower that plasma glucose concentration (de Vries et al. 2003). Previous studies have shown that BDNF levels are reduced in the hippocampus in rodent models of type 2 diabetes including leptin receptor mutant mice (Stranahan et al. 2009) and rats maintained on a high-fat plus glucose diet (Stranahan et al. 2008). Conversely, intermittent fasting induces BDNF expression in the hippocampus, which may mediate beneficial effects of intermittent fasting on hippocampal neurogenesis, synaptic plasticity, and neuroprotection (Lee et al. 2002; Arumugam et al. 2010). Our findings therefore suggest the possibility that 3OHB contributes to increased BDNF expression in response to fasting.

It was previously reported that NF-κB induces N-methyl-D-apartate receptor-mediated Bdnf gene transcription in cultured cerebellar granule cells (Lipsky et al. 2001; Marini et al. 2004). We found that 3OHB induces the nuclear translocation of the NF-κB p65 subunit and increases the interaction of the transcriptional co-activator p300 with p65 in cortical neurons. Consistent with our findings in neurons, it was recently reported that 3OHB increases NF-κB activation in calf hepatocytes (Shi et al. 2014). We found that cortical neurons treated with 3OHB exhibited enhanced recruitment of p300 to a Bdnf promoter IV sequence, and inhibitors of NF-κB and p300 blocked the ability of 3OHB to induce Bdnf gene expression. Increased mitochondrial ROS generation appears to mediate 3OHB-induced Bdnf expression because we found that agents that reduced mitochondrial superoxide levels prevented 3OHB-induced Bdnf promoter activity. Interestingly, we found that levels of two antioxidant enzymes (SOD2 and heme oxygenase 1) that are encoded by genes previously shown to be induced by NF-κB (Kiningham et al. 2001; Naidu et al. 2008) were increased in 3OHB-treated neurons. We found that 3OHB increased mitochondrial respiration in cortical neurons suggesting that up-regulation of antioxidant defenses in response to 3OHB may represent an adaptive response to cope with elevated mitochondrial ROS generation.

We found that neurons treated with BDNF exhibited an increased mitochondrial respiration rate, and that a BDNF blocking antibody prevented 3OHB-induced increases in mitochondrial respiration. It was previously reported that BDNF can increase mitochondrial respiratory coupling in rat brain mitochondria (Markham et al. 2004) and increases respiratory coupling efficiency in mouse brain synaptosomes (Markham et al. 2012). It has also been shown that when cultured rat cortical neurons are treated with 3OHB, their respiratory capacity increases and they are better able to sustain mitochondrial function when exposed to high levels of glutamate (Laird et al. 2013). Our findings suggest the neuroprotective actions of 3OHB are mediated, at least in part, by BDNF signaling. Numerous studies have shown that fasting is neuroprotective in animal models relevant to AD, PD, and HD (Duan and Mattson 1999; Duan et al. 2003; Halagappa et al., 2007; Griffioen et al. 2013), as well as stroke (Arumugam et al. 2010) and traumatic brain injury (Davis et al. 2008). If and to what extent 3OHB contributes to such neuroprotection remains to be established. However, the ability of ketogenic diets (Gasior et al. 2006; Maalouf et al. 2009) and 3OHB supplementation (Kashiwaya et al. 2013) to protect neurons and improve functional outcome in animal models of neurodegenerative conditions is consistent with an important role for 3OHB in the neuroprotective effects of fasting.

Evolutionary considerations and experimental findings suggest that cognitive function is bolstered by vigorous physical activity and food scarcity/fasting (Mattson 2015). The ability to outsmart one's competitors in the battle for limited food resources has been fundamental to the evolution of the brains of most species including humans. The integration of signaling pathways by which the brain and other organ systems respond adaptively to evolutionarily fundamental bioenergetics challenges are undoubtedly complex involving activation of CNS neural circuits, neuroendocrine pathways, and signals from peripheral organs to the brain. Emerging evidence suggests that BDNF is key mediator of adaptive responses of the brain and peripheral organ systems to bioenergetic challenges (Marosi and Mattson 2014). Our findings suggest a role for 3OHB in up-regulation of BDNF signaling in brain cells in response to exercise and fasting. We found that voluntary exercise increases plasma 3OHB levels and that there is a significant positive correlation between the concentration of circulating 3OHB and levels of BDNF in the hippocampus. Consistent with a role for 3OHB-induced BDNF expression in the neuroprotective effects of fasting and exercise in vivo, it was reported that fasting engages TrkB signaling, promotes neuroplasticity, and improves behavioral recovery after spinal cord injury (Plunet et al., 2008). For example, BDNF signaling in the CNS regulates appetite (Kernie et al. 2000), enhances peripheral insulin sensitivity (Nakagawa et al. 2000), and enhances parasympathetic regulation of heart rate (Wan et al. 2014). Because BDNF expression in multiple brain regions is increased in response to energetic challenges that elevate 3OHB levels, our finding that 3OHB acts directly on neurons to stimulate BDNF expression suggests potential roles for 3OHB in up-regulating BDNF expression under such conditions and could, by this mechanism, contribute to the beneficial effects of fasting and vigorous exercise on cognitive performance, and to improved peripheral energy metabolism and cardiovascular fitness (Wan et al. 2003; van Praag et al. 2014).

Acknowledgments and conflict of interest disclosure

We thank Erez Eitan for providing assistance with some of the experiments. This research was supported, in its entirety, by the Intramural Research Program of the National Institute on Aging. None of the authors have any conflicts of interest to declare.

All experiments were conducted in compliance with the ARRIVE guidelines.

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