**4. Primary astroglia from rodent brain and human iPS cell-derived astroglia**

Classically, cultured astroglia prepared from rats or mice have been used to assess the metabolic properties of astroglia in vitro [3]. Basal glucose consumption by cultured rodent astroglia seems to be comparable to that by cultured rodent neurons. Interestingly, however, the amount of lactate that is released into the culture media is much higher in astroglial cultures than in neuronal cultures (**Figure 5**) [3, 23],

*Astrocyte-neuron lactate shuttle hypothesis (ANLSH) (adapted from [3]).*

#### **Figure 10.**

*Glutamate stimulates [14C]deoxyglucose phosphorylation through a Na+ -dependent glutamate transporter in rat cultured astroglia (adapted from [18]).*

suggesting the occurrence of active aerobic glycolysis in astroglia. Although the glucose consumption of astroglia seems to be comparable to that of neurons, the in vivo location of astroglia in the brain may make glucose uptake more suitable [30–32]. In contrast, neurons are not in direct contact with microvessels. Therefore, avid glucose uptake by cultured neurons may not reflect glucose metabolism in vivo. Of course, glucose supplied from the microvessels diffuses into the extracellular space and can be taken up by neurons via their glucose transporters (Glut 3) (**Figure 9**) [3, 17]. In addition to glucose, lactate generated by astroglia and released into the extracellular space can also be taken up by neurons via neuronal MCT2 (**Figure 9**) [3, 17]. When both glucose and lactate are available, cultured neurons metabolize lactate preferentially (**Figures 6** and **7**) [3, 23].

*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 11.**

*Effects of L-glutamate on lactate release measured directly in culture medium for rat astroglia (adapted from [23]).*

Neuronal activation causes glutamate release in the synaptic cleft. The maximal concentration of glutamate can reach 1 mM, which is toxic to neurons. To prevent glutamate toxicity, the end-feet of astroglia, which envelope the synapse (tripartite synapse) [32], remove glutamate via glutamate transporters together with the cotransportation of Na+ based on an inwardly lower Na+ -gradient across the membrane [3, 16, 33]. This inwardly lower ionic concentration gradient is maintained by Na+ ,K+ -ATPase; thus, ATP production requires glucose as an energy substrate. So far, cultured astroglia typically show high glucose utilization and lactate production, and these profiles are exaggerated by the addition of glutamate. Recently, we evaluated astroglia that had differentiated from human induced-pluripotent stem (iPS) cells and observed the conservation of similar metabolic profiles [54]. These results suggest that glutamate uptake enhances the consumption of glycolysisderived ATP. Of note, glutamate in astroglia is converted into glutamine and recycled back to neurons (glutamate-glutamine cycle) (**Figure 5**) [3]. In addition, some of this glutamate is converted to alfa-ketoglutarate and utilized as a TCA cycle substrate (**Figure 12**) [3–5]. The capacity for glutamate oxidation is greater in astroglia than in neurons (**Figure 13**) [unpublished data]. Moreover, recent findings

*Glutamate taken up by Na+ -dependent glutamate transporters enhances astroglial energy metabolism (both glycolytic and/or oxidative) (adapted from [3]).*

*[1-14C]glutamate oxidation (CO2 production from glutamate) in astroglia and neurons.*

suggest that malate, an intermediate TCA metabolite, contributes to lactate production through its conversion into lactate via malic enzyme (**Figure 14**) [3].
