Glucose is the main energy substrate for the brain, which accounts for about 20% of whole-body glucose utilization. Glucose is metabolized in cells either by glycolysis or the pentose phosphate pathway (PPP). In the glycolytic pathway, glucose is converted to pyruvate which can be converted to lactate or sent to the tricarboxylic acid (TCA) cycle to generate ATP via oxidative phosphorylation. Alternatively, glucose can enter the PPP to generate 5-carbon sugars, as well as NADPH, which is a cofactor for cholesterol biosynthesis and protects against oxidative stress. Though each cell can use glucose for either glycolysis or the PPP, different cell populations favor distinct metabolic pathways. For example, oligodendrocytes shuttle more glucose into the PPP in order to generate NADPH for cholesterol biosynthesis, which is then used to build up myelin sheaths.
To investigate the regional fate of glucose, Kleinridders, Ferris, Reyzer et al. assessed multiple steps within the glycolytic pathway and PPP using a combination of gene and protein expression, protein activity assays, and imaging mass spectrometry (IMS). They demonstrate that while measurements of enzyme expression and activity point to differences in the regional activity of glycolysis and the PPP, IMS provides a direct measurement of the metabolites generated in these pathways in specific brain regions, including those which are otherwise difficult to assess, such as the fimbria or corpus callosum. Further, they show that in these highly myelinated white matter tracts there is a high ATP/ADP ratio but not a similarly high hexose bisphosphate/hexose monophosphate ratio, supporting the notion that the lactate shuttle may be very important for energy metabolism in these brain regions.