Lactate muscles its way into consciousness: fueling brain activation.

THE ENERGETICS OF NEURON-ASTROCYTE interactions during brain activation is an exciting but controversial topic because the idea that lactate might be a significant supplemental fuel challenges the long-held consensus that brain is strictly dependent on glucose as its obligatory fuel. Thus a “cellular menu” comprised of “sweet and sour food for thought” could be envisaged in which the traditional sweet brain foods, glucose and glycogen, might be combined with a sour ingredient, lactate, which is derived from glycolytic metabolism of glucose either within the brain, as proposed by studies described below, or by muscles during vigorous exercise, as reported in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology by Dalsgaard and colleagues (12). The uptake by brain of muscle-derived lactate during intense physical activity extends the “cell-cell and intracellular” lactate shuttle concepts recently reviewed by Brooks (4), in which lactate is recognized not as simply a dead-end metabolite formed during hypoxic-anoxic conditions, but rather, as an energy-rich intermediate or a precursor for gluconeogenesis that can be transferred within and among in normal, normoxic body tissues to maximize overall energy efficiency. Thus the flow of glucose-derived carbon through the glycolytic and oxidative pathways needs not be continuous in a given cell, tissue, or organ. Instead, glycolysis might predominate in some subcellular structures, cells, regions, or conditions, whereas oxidative metabolism and resynthesis of glucose from circulating lactate might prevail in others. The possibility of activity-dependent and temporal-spatial partitioning of brain metabolism is an idea that has been evolving over time as different types of studies help elucidate the functional and interactive architecture of the brain’s cellular, neurotransmitter, and enzymatic systems (1, 3, 6–8, 14–16, 20, 21, 26, 35, 36). It is well established that blood-borne glucose is the obligatory fuel for brain and, to satisfy the moment-to-moment changes in energy demand during information processing, the local rates of blood flow and glucose utilization are closely linked to the activities of brain cells; this coupling provides a means to measure functional activity under normal and pathophysiological conditions by metabolic imaging techniques (40). Because the blood-brain barrier restricts transfer of material from blood into brain, many compounds that are readily metabolized by cultured brain cells or brain slices, including lactate, cannot be transported into adult brain in vivo in sufficient quantities to compensate for inadequate levels of glucose and support the brain’s high and continuous energy demand. For this reason, the possibility that lactate synthesized within the brain might have an important role as an energy source during brain activation has received a lot of attention. This interest has been spurred by many types of studies, including support of synaptic function by lactate in brain slices (38); substrate transport and metabolism studies in cultured astrocytes and neurons carried out in many laboratories; and by a model, the key elements of which are derived from studies in cultured astrocytes, that portrays an astrocyte-neuron metabolic unit in which excitatory glutamatergic neurotransmission is linked to shuttling of lactate produced by astrocytes to neurons for oxidation (31, 35, 36). However, there are many critical unresolved issues related to this model (6, 14–16, 20, 21), especially two major concerns. First, metabolic responses to glutamate exposure by astrocyte cultures grown in different laboratories are not consistent in magnitude or direction, suggesting differences in oxidative capacity or other properties of various astrocyte preparations and uncertainties of extrapolation of data obtained in vitro to characterize astrocytes that mature in vivo and function in their natural environment. Second, there is no direct experimental evidence for a targeted transfer of significant quantities of lactate specifically from one cell type to another in normal working brain in vivo. Furthermore, the disproportionate increase in the rate of utilization of glucose (CMRglc) compared with oxygen (CMRO2) in working brain in vivo (see below) demonstrates that there cannot be a tight spatial-temporal relationship between lactate synthesis and its oxidation in neighboring brain cells because oxygen consumption fails to match glucose utilization during activation. There are, however, normal physiological conditions in which lactate produced outside the brain can be a significant fuel, and an interesting series of studies designed, in part, to evaluate the energy cost of mental effort and central fatigue in human brain during and after vigorous physical activity by the Secher laboratory (reviewed in Ref. 34) has put a spotlight on muscle-derived lactate as a brain energy substrate during physical exertion. A striking and unexpected finding during exhaustive exercise in humans, which causes blood lactate levels to rise markedly, is that uptake of lactate into brain is consistently associated with a substantial downward shift in the ratio of oxygen to carbohydrate utilization (10, 11, 34). Because lactate is an oxidative fuel and brain is generally considered to be a highly oxidative organ, uptake and metabolism of lactate derived from peripheral sources would be expected to raise oxygen consumption in proportion to the carbohydrate taken up into brain. Instead, as shown by Dalsgaard and colleagues (12) in this issue, the respiratory quotient is about one during both rest and exercise, indicating that carbohydrate is the major brain fuel, and the metabolic ratio, calculated as (oxygen/ [glucose 1/2 lactate]) from measured arteriovenous differences across the brain, falls from a resting value of about six (the theoretical maximum) to about three during forceful exercise; conceivably, this ratio might be reduced further if pyruvate released to blood by working muscle (24) is also taken up by brain. Despite its substantial uptake, lactate was previously shown not to accumulate in brain tissue or cerebrospinal fluid (11), suggesting that it is oxidized, perhaps sparing glucose for other uses. The quantity of the glucose taken up in Address for reprint requests and other correspondence: G. A. Dienel, Dept. of Neurology, Slot 830, Univ. of Arkansas for Medical Sciences, 4301 W. Markham St., Shorey Bldg., Rm. 715, Little Rock, AR 72205 (E-mail: [email protected]). Am J Physiol Regul Integr Comp Physiol 287: R519–R521, 2004; 10.1152/ajpregu.00377.2004.