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Lactate and the brain: the neonate

Lactate-Balls-JPEG-1024x948Lactate seems to be able to produce C02 efficiently, at least in the context of the early postnatal period. What is interesting is that blood lactate doesn’t seem to be elevated. Yet it is being oxidized preferentially over glucose. Glucose seems to be being spared for specialized precursors. It is also interesting that lactate doesn’t seem to be going through the Cori cycle but straight to the Krebs (Medina, 1985), which is interesting because it might mean these early adaptive responses are not in the same stressful context such as working muscles? Much like producing ketones from ketogenic fatty acids is not stressful.

Dombrowski, G. J., Swiatek, K. R., & Chao, K. L. (1989). Lactate, 3-hydroxybutyrate, and glucose as substrates for the early postnatal rat brain. Neurochemical research, 14(7), 667–75. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2779727

The dependence of cerebral energy metabolism upon glucose, 3-hydroxybutyrate, and lactate as fuel sources during the postnatal period was investigated. The brain of 6 day old suckling pups used very little glucose, but by the 15th postnatal day glucose was the major catabolite. Hydroxybutyrate was not a major brain fuel at either 6 or 15 days of age. Its utilization accounted for only 19% of the brain’s total energy needs at 15 days of age, even through blood ketone concentrations are near maximal at this time. Seventy percent of the cerebral metabolic requirements were met by lactate in animals aged 6 days. The major role played by lactate as a substrate for brain metabolism in young pups was not a result of abnormally elevated blood lactate concentrations. The slow catabolism of glucose in young brain can not be explained by low rates of influx or inadequate enzymatic capacity.

Fernández, E., & Medina, J. M. (1986). Lactate utilization by the neonatal rat brain in vitro. Competition with glucose and 3-hydroxybutyrate. The Biochemical journal, 234(2), 489–92. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1146593&tool=pmcentrez&rendertype=abstract

The maximum rates of lactate oxidation and lipogenesis from lactate by early-neonatal brain slices were considerably greater than those for utilization of glucose and 3-hydroxybutyrate at physiological concentrations. Lactate inhibited glucose utilization, but enhanced 3-hydroxybutyrate utilization. 3-Hydroxybutyrate inhibited lactate and glucose utilization. Glucose slightly inhibited oxidation of lactate and 3-hydroxybutyrate, but scarcely enhanced lipogenesis from these substrates.

Holmgren, C. D., Mukhtarov, M., Malkov, A. E., Popova, I. Y., Bregestovski, P., & Zilberter, Y. (2010). Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro. Journal of neurochemistry, 112(4), 900–12. doi:10.1111/j.1471-4159.2009.06506.x

While the ultimate dependence of brain function on its energy supply is evident, how basic neuronal parameters and network activity respond to energy metabolism deviations is unresolved. The resting membrane potential (E(m)) and reversal potential of GABA-induced anionic currents (E(GABA)) are among the most fundamental parameters controlling neuronal excitability. However, alterations of E(m) and E(GABA) under conditions of metabolic stress are not sufficiently documented, although it is well known that metabolic crisis may lead to neuronal hyper-excitability and aberrant neuronal network activities. In this work, we show that in slices, availability of energy substrates determines whether GABA signaling displays an inhibitory or excitatory mode, both in neonatal neocortex and hippocampus. We demonstrate that in the neonatal brain, E(m) and E(GABA) strongly depend on composition of the energy substrate pool. Complementing glucose with ketone bodies, pyruvate or lactate resulted in a significant hyperpolarization of both E(m) and E(GABA), and induced a radical shift in the mode of GABAergic synaptic transmission towards network inhibition. Generation of giant depolarizing potentials, currently regarded as the hallmark of spontaneous neonatal network activity in vitro, was strongly inhibited both in neocortex and hippocampus in the energy substrate enriched solution. Based on these results we suggest the composition of the artificial cerebrospinal fluid, which bears a closer resemblance to the in vivo energy substrate pool. Our results suggest that energy deficits induce unfavorable changes in E(m) and E(GABA), leading to neuronal hyperactivity that may initiate a cascade of pathological events.

Medina, J. M. (1985). The role of lactate as an energy substrate for the brain during the early neonatal period. Biology of the neonate, 48(4), 237–44. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3904842

The role played by lactate as an energy substrate for the newborn rat during the early neonatal period was studied. Plasma lactate is mostly removed within the first 2 h after delivery, i.e. during the presuckling period. Lactate removal was enhanced by hyperoxia but strongly inhibited by hypoxia, showing a direct correlation with blood oxygen concentrations. Lactate was not converted into glucose during the presuckling period, gluconeogenesis being insignificant in these circumstances; instead it was rapidly oxidized through the tricarboxylic acid cycle. Likewise, lactate was significantly oxidized by brain slices from newborns at birth. At physiological concentrations, lactate oxidation by brain slices was 10- and 3-fold higher than that of glucose and 3-hydroxybutyrate, respectively. In the same circumstances, lipogenesis de novo from lactate was 2- and 5-fold higher than from glucose and 3-hydroxybutyrate, respectively. The results suggest that lactate is the main metabolic fuel for the brain during the early neonatal period.

Vicario, C., Arizmendi, C., Malloch, G., Clark, J. B., & Medina, J. M. (1991). Lactate utilization by isolated cells from early neonatal rat brain. Journal of neurochemistry, 57(5), 1700–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1919582

The utilization of lactate, glucose, 3-hydroxybutyrate, and glutamine has been studied in isolated brain cells from early newborn rats. Isolated brain cells actively utilized these substrates, showing saturation at concentrations near physiological levels during the perinatal period. The rate of lactate utilization was 2.5-fold greater than that observed for glucose, 3-hydroxybutyrate, or glutamine, suggesting that lactate is the main metabolic substrate for the brain immediately after birth. The apparent Km for glucose utilization suggested that this process is limited by the activity of hexokinase. However, lactate, 3-hydroxybutyrate, and glutamine utilization seems to be limited by their transport through the plasma membrane. The presence of fatty acid-free bovine serum albumin (BSA) in the incubation medium significantly increased the rate of lipogenesis from lactate or 3-hydroxybutyrate, although this was balanced by the decrease in their rates of oxidation in the same circumstances. BSA did not affect the rate of glucose utilization. The effect of BSA was due not to the removal of free fatty acid, but possibly to the binding of long-chain acyl-CoA, resulting in the disinhibition of acetyl-CoA carboxylase and citrate carrier.

Vicario, C., & Medina, J. M. (1992). Metabolism of lactate in the rat brain during the early neonatal period. Journal of neurochemistry, 59(1), 32–40. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1613508

The metabolism of lactate in isolated cells from early neonatal rat brain has been studied. In these circumstances, lactate was mainly oxidized to CO2, although a significant portion was incorporated into lipids (78% sterols, 4% phosphatidylcholine, 2% phosphatidylethanolamine, and 1% phosphatidylserine). The rate of lactate incorporation into CO2 and lipids was higher than those found for glucose and 3-hydroxybutyrate. Lactate strongly inhibited glucose oxidation through the pyruvate dehydrogenase-catalyzed reaction and the tricarboxylic acid cycle while scarcely affecting glucose utilization by the pentose phosphate pathway. Lipogenesis from glucose was strongly inhibited by lactate without relevant changes in the rate of glycerol phosphate synthesis. These results suggest that lactate inhibits glucose utilization at the level of the pyruvate dehydrogenase-catalyzed reaction, which may be a mechanism to spare glucose for glycerol and NADPH synthesis. The effect of 3-hydroxybutyrate inhibiting lactate utilization only at high concentrations of 3-hydroxybutyrate suggests that before ketogenesis becomes active, lactate may be the major fuel for the neonatal brain. (-)-Hydroxycitrate and aminooxyacetate markedly inhibited lipogenesis from lactate, suggesting that the transfer of lactate carbons through the mitochondrial membrane is accomplished by the translocation of both citrate and N-acetylaspartate.

Adam, P. A., Räihä, N., Rahiala, E. L., & Kekomäki, M. (1975). Oxidation of glucose and D-B-OH-butyrate by the early human fetal brain. Acta paediatrica Scandinavica, 64(1), 17–24. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1114894

The isolated brains of 12 previable human fetuses obtained at 12 to 21 weeks’ gestation, were perfused through the interval carotid artery with glucose (3 mM) and/or DL-B-OH-butyrate (DL-BOHB), 4.5 MM, plus tracer quantities of either glucose-6-14C (G6-14C) or beta-OH-butyrate-3-14C (BOHB3-14C). Oxidative metabolism was demonstrated by serial collection of gaseous 14CO2 from the closed perfusion system, and from the recirculating medium. Glucose and BOHB were utilized at physiological rates as indicated (mean plus or minus SEM): G6-14C at 0.10 plus or minus 0.01 mumoles/min g brain (n equal 7) or 17.5 plus or minus 1.9 mumoles/min kg fetus; and BOHB3-14C at 0.16 plus or minus 0.05 mumoles/min g (n equal to 5) or 27.3 plus or minus 7.4 mumoles/min kg. Based on fetal weight, glucose metabolism by brain apparently accounted for about 1/3 of basal glucose utilization in the fetus. On a molar basis BOHB3-14C was taken up at 1.47 times the rate of G6-14C. Both BOHB3-14C and G6 14C were converted to 14CO2. The rate of BOHB3-14C conversion to 14CO2 was equal to its rate of consumption, and exceeded the conversion of glucose to CO2 because 45% of the G6-14C was incorporated into lactate-14C. Accordingly, both substrates support oxidative metabolism by brain; and BOHB is a major potential alternate fuel which can replace glucose early in human development.

Freinkel, N., Cockroft, D. L., Lewis, N. J., Gorman, L., Akazawa, S., Phillips, L. S., & Shambaugh, G. E. (1986). The 1986 McCollum award lecture. Fuel-mediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture. The American journal of clinical nutrition, 44(6), 986–95. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3788845

Whole rat embryos were explanted at head-fold, late pre-somite stage (day 9.5 of gestation) and cultured in rat sera varyingly supplemented with glucose (3, 6, 9, or 12 mg/mL), D,L sodium beta-hydroxybutyrate (2, 4, 8, or 16 mM), or both (6 mg/mL D-glucose plus 8 mM beta-hydroxybutyrate). During 48 h culture, increasing glucose alone or beta-hydroxybutyrate alone effected growth retardation and faulty neural and extraneural organogenesis in dose-dependent fashion. Synergistic dysmorphogenic effects occurred when minimally teratogenic concentrations of glucose and beta-hydroxybutyrate were combined. Sera from diabetic animals containing somatomedin inhibitor bioactivity were also able to produce growth retardation and major developmental lesions in presence of amounts of glucose and ketones which of themselves were not teratogenic. Thus, aberrant fuels and fuel-related products can impair growth and organogenesis in early post-implantation embryo. Such fuel-mediated teratogenesis may be multifactorial and include possibilities for synergistic and additive interactions.

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