Abstract
Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.
Highlights
The study of mammalian brain bioenergetics has centered on the transport of glucose and its metabolism in the presence of oxygen
This hypothesis suggests that the increased brain extracellular glucose is the result of decreased glycolysis since, as we previously indicated, gluconeogenesis is a costly, energy-dependent process (Katz, 1985)
We are aware that our observations, as they stand, cannot be used to establish the relative prominence of the hypotheses we entertained in the discussion because we did not measure glucose or lactate utilization within the different brain metabolic pathways nor did we measure the brain levels of most of the systemically injected substances
Summary
The study of mammalian brain bioenergetics has centered on the transport of glucose and its metabolism in the presence of oxygen. Modeled from the lactate shuttle in muscles (Brooks, 1986, 2000; Brooks et al, 1999; Giugliano et al, 2008), the Astrocyte-to-Neuron Lactate Shuttle (ANLS) hypothesis was first proposed by Pellerin and Magistretti (1994). This hypothesis postulates that in times of increased neuronal activity, and energy demand, astrocytes take up blood glucose via their well-positioned endfeet on capillaries and convert this glucose to lactate. Lactate is shuttled to surrounding neurons for oxidative phosphorylation, avoiding the glycolytic steps involved in the full metabolism of glucose
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