Cerebral metabolism of lactate in vivo: Evidence for neuronal pyruvate carboxylation

The cerebral metabolism of lactate was investigated. Awake mice received [3 -C-13]lactate or [1-C-13]glucose intravenously, and brain and blood extract s were analyzed by C-13 nuclear magnetic resonance spectroscopy. The cerebr al uptake and metabolism of [3-C-13]lactate was 50% that of [1-C-13]glucose . [3-C-13]Lactate was almost exclusively metabolized by neurons and hardly at all by glia, as revealed by the C-13 labeling of glutamate, gamma-aminob utyric acid and glutamine. Injection of [3-C-13]lactate led to extensive fo rmation of [2-C-13]lactate, which was not seen with [1-C-13]glucose, nor ha s it been seen in previous studies with [2-C-13]acetate. This formation pro bably reflected reversible carboxylation of [3-C-13]pyruvate to malate and equilibration with fumarate, because inhibition of succinate dehydrogenase with nitropropionic acid did not block it. Of the [3-C-13]lactate that reac hed the brain, 20% underwent this reaction, which probably involved neurona l mitochondrial malic enzyme. The activities of mitochondrial malic enzyme, fumarase, and lactate dehydrogenase were high enough to account for the fo rmation of [2-C-13]lactate in neurons. Neuronal pyruvate carboxylation was confirmed by the higher specific activity of glutamate than of glutamine af ter intrastriatal injection of [1-C-14]pyruvate into anesthetized mice. Thi s procedure also demonstrated equilibration of malate, formed through pyruv ate carboxylation, with fumarate. The demonstration of neuronal pyruvate ca rboxylation demands reconsideration of the metabolic interrelationship betw een neurons and glia.