Cerebral metabolism of lactate in vivo: evidence for neuronal pyruvate carboxylation.
The cerebral metabolism of lactate was investigated. Awake mice received [3-13C]lactate or [1-13C]glucose intravenously, and brain and blood extracts were analyzed by 13C nuclear magnetic resonance spectroscopy. The cerebral uptake and metabolism of [3-13C]lactate was 50% that of [1-13C]glucose. [3-13C]Lactate was almost exclusively metabolized by neurons and hardly at all by glia, as revealed by the 13C labeling of glutamate, gamma-aminobutyric acid and glutamine. Injection of [3-13C]lactate led to extensive formation of [2-13C]lactate, which was not seen with [1-13C]glucose, nor has it been seen in previous studies with [2-13C]acetate. This formation probably reflected reversible carboxylation of [3-13C]pyruvate to malate and equilibration with fumarate, because inhibition of succinate dehydrogenase with nitropropionic acid did not block it. Of the [3-13C]lactate that reached the brain, 20% underwent this reaction, which probably involved neuronal mitochondrial malic enzyme. The activities of mitochondrial malic enzyme, fumarase, and lactate dehydrogenase were high enough to account for the formation of [2-13C]lactate in neurons. Neuronal pyruvate carboxylation was confirmed by the higher specific activity of glutamate than of glutamine after intrastriatal injection of [1-14C]pyruvate into anesthetized mice. This procedure also demonstrated equilibration of malate, formed through pyruvate carboxylation, with fumarate. The demonstration of neuronal pyruvate carboxylation demands reconsideration of the metabolic interrelationship between neurons and glia.
Hassel
B
B
Division for Environmental Toxicology, Norwegian Defense Research Establishment, Kjeller, Norway.
Bråthe
A
A
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D002244:Carbon / Q000378:metabolism; D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D002450:Cell Communication / Q000502:physiology; D003600:Cytosol / Q000201:enzymology; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000502:physiology; D005260:Female; D005650:Fumarates / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D019344:Lactic Acid / Q000097:blood* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008291:Malate Dehydrogenase / Q000378:metabolism*; D008293:Malates / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000201:enzymology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D013574:Synaptosomes / Q000201:enzymology
D001786:Blood Glucose; D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D005650:Fumarates; D008293:Malates; D019344:Lactic Acid; D002244:Carbon; C030298:malic acid; D019289:Pyruvic Acid; C032005:fumaric acid; D008291:Malate Dehydrogenase; C030574:malate dehydrogenase (decarboxylating); D005947:Glucose