Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse

Abstract

Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.

Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

“…38,39 Astrocytes internalize lactate via MCT1/4 but the concentration of the blocker used in our study blocks only neuronal MCT2. 23,40 The concentration of glucose used was necessary to induce and maintain the epileptiform activity in slices due to the differences in metabolite diffusion in the in vitro brain slice preparation as compared to the intact brain. Of late, lactate is considered as a signaling molecule rather than the normally held view of its role as a metabolite.…”

“…In our study, the inhibitory effect of lactate is not due to the glucose concentration used in external solution, as studies have shown that systemic increase in glucose concentration does not lead to significant increase in lactate concentration in brain extracellular space. 23,40 The concentration of glucose used was necessary to induce and maintain the epileptiform activity in slices due to the differences in metabolite diffusion in the in vitro brain slice preparation as compared to the intact brain. 3,5-DHBA reduced the spike frequency; however, unlike lactate it did not result in hyperpolarization of subicular neurons, which can be due to various possibilities like the shift in membrane potential can be partially dependent on the intracellular cAMP level that is downregulated by lactate-HCA1-G i signaling.…”

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

“…Moreover, the balance between blood and brain cells may differ between the brain homogenates of control and mutant mice. As lactate concentrations in the blood are two- to three-fold higher than those in the mouse brain (extracellular compartment) ( Béland-Millar et al , 2017 ), such differences may represent an additional confounding factor. Although differences in genetic background are also of concern when making comparisons between different mouse strains ( Wolfer et al , 2002 ), we utilized over nine backcrossings in addition to littermates within each strain.…”

Limitations and Challenges in Modeling Diseases Involving Spinal Motor Neuron Degeneration in Vitro

“…Peripherally produced insulin-like growth factor-1 crosses the blood–brain barrier and enhances the neuroprotective potential of astrocytes through binding to the receptors expressed on their cell membranes ( Ang et al, 1993 ; Gray et al, 2017 ). Lactate released by astrocytes is believed to be taken up and utilized as an energy source by neurons ( Béland-Millar et al, 2017 ). Other important functions of astrocytes include clearance of excess glutamate from the inter-synaptic space to prevent neuronal damage due to hyper-excitation ( Barres, 1991 ).…”