**5. Fates of lactate produced by astroglia**

Whether lactate produced and released from astroglia can be used as an energy substrate by neurons has long been debated [36–53]. Theoretically, MCT4 in astroglia *Lactate and Ketone Bodies Act as Energy Substrates as Well as Signal Molecules in the Brain DOI: http://dx.doi.org/10.5772/intechopen.97035*

#### **Figure 14.**

*Glutamate taken up by Na+ -dependent glutamate transporters enhances lactate production through a glycolytic pathway as well as through malic enzyme activation in astroglia (adapted from [3]).*

#### **Figure 15.**

*Increasing lactate concentrations (1–3 mM) enhance [14C]lactate oxidation in cultured neurons (adapted from [23]).*

export lactate outside such cells, and MCT2 in neurons take up lactate [3, 17]. Once lactate enters a neuron, it could become a preferential energy substrate, compared with glucose; this pathway is known as the astrocyte-neuron lactate shuttle model (**Figure 5**) [3, 33]. In our in vitro culture model, increasing the concentrations of lactate enhanced the neuronal oxidation of lactate (**Figure 15**) [23]. The argument against this model is based on the high affinity of MCT2, which results in the rapid saturation of lactate transportation into neurons [52, 53]. Thus, astroglial lactate production does not favor neuronal lactate utilization. The validity of this model should be elucidated in vivo.

Lactate plays a role as a signal molecule. BDNF expression can also be induced by lactate through the activation of Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC-1α and the secreted molecule FNDC5, known to mediate BDNF expression [13, 14]. Moreover, hydroxycarboxylic acid receptor 1 (HCAR1) has been found to act as a lactate receptor that results in the suppression of neuronal activity [55–57]. Lauritzen et al. showed that HCAR1 at the BBB was essential for mediating the effects of exercise on angiogenesis in a mouse model [56]. Furthermore, lactate binding to HCAR1 on neurons inhibits adenylate cyclase and thus decreases cAMP, thereby reducing neuronal activity and gene regulation. The potential negative modulation of BDNF production by lactate through HCAR1 should be examined more closely in the future.

## **6. Astroglia produce ketone bodies, which serve as neuronal energy substrates**

In addition to BHB, acetoacetate and acetone are listed as ketone bodies. During starvation, ketone body production by hepatocytes in the liver is enhanced [3–5]. Astroglia in the brain function similar to hepatocytes and generate more ketone bodies than neurons (**Figure 16**) [3, 25]. The production of BHB is regulated by the AMP/ATP level, or the cellular energy state. AMP-activated protein kinase (AMPK) can sense a decrease in ATP and the resultant increase in AMP, which induces the activation of AMPK. Decreased malonyl-CoA stimulates the beta-oxidation of long-chain fatty acids, enhancing the production of acetoacetate and BHB. 5-Amino-1-b-D-ribofuranosylimidazole-4-carboxamide (AICAR), an activator of AMPK, stimulates these two ketone bodies in astroglia (**Figure 17**) [3, 25]. Similar to lactate, BHB is exported via MCT4 and is then imported into neurons through MCT2 and used as an alternative energy substrate [3, 17]. Unlike glucose-derived lactate, which needs to be converted to acetyl-CoA by PDHC to enter the TCA cycle, BHB enters the TCA cycle in an PDHC-independent manner. PDHC is susceptible to cellular stressors like reactive oxygen species (ROSs). Enhanced lactate production under brain ischemia triggers the accumulation of lactate. Unfortunately, however, re-perfusion therapy might not be helpful when PDHC is

**Figure 16.**

*[1-14C]palmitic acid (PA) derived-CO2 and acid-soluble fractions (ketone bodies: KBs) in rat neurons and astroglia (adapted from [25]).*

*Lactate and Ketone Bodies Act as Energy Substrates as Well as Signal Molecules in the Brain DOI: http://dx.doi.org/10.5772/intechopen.97035*

#### **Figure 17.**

*Ketogenesis by astroglia and neurons by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a cell-permeable activator of AMPK (500 μM) (adapted from [25]).*

#### **Figure 18.**

*Effects of 1% hypoxia (24 h) on oxidative metabolism of lactate (LAC), pyruvate (PYR), or*  β*-hydroxybutyrate (BHB) in neurons (adapted from [25]). Neuronal utilization (oxidative metabolism) of LAC and PYR was significantly reduced after hypoxia, while BHB oxidation was preserved.*

damaged, since lactate is incapable of being utilized even in the presence of re-supplied oxygen (**Figure 18**). In contrast, neurons can utilize BHB instead of lactate, and ATP production can be restored after re-oxygenation (**Figure 18**) [3, 25].

#### **7. BHB acts as an HDAC inhibitor and as a ligand of HCAR2**

Vigorous physical exercise induces BHB production by the liver, but astroglial BHB production under similar conditions has not been confirmed. Liver-derived BHB acts as a direct Class I HDAC inhibitor. By inhibiting HDAC2 and HDAC3 and preventing their recruitment to the BDNF promoter I, BHB induces BDNF expression [15, 16]. As described above, ischemic insults do, indeed, activate astroglial BHB production. Therefore, BHB-induced BDNF may help neuronal regeneration after ischemic damage. Further study is warranted. BHB released from astroglia also acts as a ligand of hydroxycarboxylic acid receptor 2 (HCAR2) and exerts neuroprotective effects by activating HCAR2, which in turn promotes the downstream activation of silent information regulator 1 (SIRT1) and inhibits nuclear factor-kappa B (NFκB) to protect against oxidative stress [58–61].
