A better understanding of the molecular basis of brain energy metabolism is critically relevant to properly interpret functional imaging data and advance the knowledge of cellular mechanisms underlying several neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s diseases). Glucose, the main source of energy in the brain, is cooperatively used, metabolized and shared between two main cell types: astrocytes and neurons. Based on previous experimental data, we evaluate the possibility that pH fluctuations regulate glucose metabolism. Our research strategy is based on a Systems Biology approach that combines in silico modeling of glucose metabolism with high-resolution imaging techniques of metabolic biosensors expressed in the brain of mice. Our long-term goal is to integrate three features in a single dynamic model of brain energy metabolism: intracellular metabolic fluxes, intercellular transfer of energy equivalents and activity-dependent regulation.