The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study

Abstract

Energy metabolism in the human brain is not fully understood. Classically, glucose is regarded as the major energy substrate. However, lactate (conventionally a product of anaerobic metabolism) has been proposed to act as an energy source, yet whether this occurs in man is not known. Here we show that the human brain can indeed utilize lactate as an energy source via the tricarboxylic acid cycle. We used a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C substrates into the brain and recover (13)C metabolites from the brain, and high-resolution (13)C nuclear magnetic resonance. Microdialysis catheters were placed in the vicinity of focal lesions and in relatively less injured regions of brain, in patients with traumatic brain injury. Infusion with 2-(13)C-acetate or 3-(13)C-lactate produced (13)C signals for glutamine C4, C3 and C2, indicating tricarboxylic acid cycle operation followed by conversion of glutamate to glutamine. This is the first direct demonstration of brain utilization of lactate as an energy source in humans.

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

“…Lactate receives attention in the TBI literature owing to the predictive value of the LPR for metabolic status and clinical outcome, and TBI reports have considered the possibility that lactate serves as neuronal oxidative fuel (Figure 1), 9,24,[29][30][31][32][33][34] in accordance with the astrocyte-to-neuron lactate (ANL) shuttle model ( Figure 2A). 35 Figure 2A) predicts (i) metabolic compartmentation during brain activation coupled with glutamate-glutamine cycling, i.e., glutamate-evoked glycolysis to fuel Na + extrusion from astrocytes ( Figure 2C), lactate transfer to neurons, and neuronal lactate oxidation, with little or no rise in neuronal glycolysis; (ii) the rise in CMR O2 should stoichiometrically match the increase in CMR glc if lactate is locally oxidized; and (iii) metabolic assays of oxidative metabolism with labeled glucose or oxygen during activation should have a magnitude similar to assays of the hexokinase step using deoxyglucose (DG) (i.e., no loss of labeled lactate, which causes underestimation of calculated CMR glc and reduces CMR O2 owing to the substrate efflux).…”

“…For example, cognitive effects may arise from lactate-evoked redox signaling pathways that alter NAD + and NADH levels and influence gene expression via their interactions with transcription factors. [120][121][122] Lactate Oxidation after Traumatic Brain Injury Gallagher et al 30 assessed metabolism of 13 C-substrates after infusion into TBI patient brain by microdialysis and reported qualitative detection of oxidative and glycolytic metabolism, i.e., label incorporation into glutamine from acetate and lactate and into lactate (curiously, not glutamine) from glucose. Extension of this approach to establish quantitative substrate contributions to overall metabolism will be very difficult because of the low temporal sensitivity and inability to assess intracellular metabolites.…”

Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

“…Lactate is a valuable energy source for the brain during euglycemia (7)(8)(9) and may be critical to maintaining brain function during severe hypoglycemia (10). Administration of lactate during hypoglycemia impairs hypoglycemic symptoms, attenuates counterregulatory hormone responses, and preserves cognitive function, mirroring the changes seen in subjects with IAH (11,12).…”

13C Magnetic Resonance Spectroscopy in Neurobiology - Its Use in Monitoring Brain Energy Metabolism and in Identifying Novel Metabolic Substrates and Metabolic Pathways

“…Even so, a number of substrates may feed into the glycolytic pathway or the TCA cycle of brain cells. For example, lactate, which was shown by 13 C MRS to be a substrate for brain metabolism in mice (Hassel and Bråthe, 2000), was recently shown by 13 C MRS to contribute importantly to energy metabolism in the human brain under physiological conditions (Gallagher et al, 2009;Boumezbeur et al, 2010). The ability of a substrate to function as a metabolic substrate for brain cells depends on its ability to cross the blood-brain barrier, i.e.…”