Brain lactate metabolism: the discoveries and the controversies

Abstract

Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-to-blood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain.

Figure 1

Multifunctional roles of glucose metabolism. Color coding denotes different functional roles of pathways of glucose metabolism. Glucose (Glc) and lactate (Lac) plus H⁺ are transported into brain cells from blood or extracellular fluid (ECF) by equilibrative transporters, GLUTs and MCTs (monocarboxylic acid transporters), respectively, whereas oxygen diffuses into brain cells. Energetics (blue) involves ATP production by the glycolytic (glucose to pyruvate; Fru=fructose) and oxidative (pyruvate to CO₂ + H₂O) pathways. Glycolytic rate is modulated by regulation of hexokinase (HK), phosphofructokinase (PFK), and other enzymes. Glucose is stored as glycogen, mainly in astrocytes. Pyruvate enters the oxidative pathway of the mitochondrial tricarboxylic acid cycle, with formation of 3 CO₂ and regeneration of oxaloacetate (OAA). Neurotransmitters and neuromodulators (brown) are synthesized through the glycolytic and oxidative pathways. Other biosynthetic pathways produce amino acids (green) and sugars (not shown) used to synthesize complex carbohydrates for glycoproteins and glycolipids. Net synthesis of a ‘new' four- or five-carbon compound (aspartate, glutamate, glutamine, GABA) requires pyruvate carboxylase (PC), which is only located in astrocytes. CO₂ fixation by PC converts pyruvate to OAA. OAA is transaminated to form aspartate or it condenses with acetyl CoA derived from a second pyruvate molecule by the action of pyruvate dehydrogenase (PDH) to form citrate (CIT). Decarboxylation of this ‘new' six-carbon compound forms α-ketoglutarate (αKG) that can be converted to a new molecule of glutamate, glutamine, and GABA. These compounds can also incorporate label from labeled glucose in neurons and astrocytes by means of reversible exchange reactions, but their net synthesis requires the astrocytic PC reaction. Acetylcholine is also derived from glucose through citrate in neurons. Entry of glucose-6-P into the pentose phosphate shunt pathway (purple) results in oxidative decarboxylation of carbon one of glucose and generates NADPH, which is used to detoxify reactive species that can cause oxidative stress. The nonoxidative branch of pentose shunt produces fructose-6-phosphate (Fru-6-P) and triose-P that reenter the glycolytic pathway; nucleotide precursors are also generated by the pentose shunt pathway. NAD⁺ is required for glycolysis, and it is regenerated from NADH by the malate–aspartate shuttle (MAS) or lactate dehydrogenase (LDH) (purple). The MAS redox shuttle transfers reducing equivalents from the cytosol to the mitochondria and is required to generate pyruvate for oxidation by the tricarboxylic acid cycle; it is also required for oxidative metabolism of lactate. Regeneration of NAD⁺ by LDH removes pyruvate from the oxidative pathway.