Differential metabolic adaptations of brain cells to feeding a ketogenic diet in mice

It is largely unknown how cells in the central nervous system (CNS) adapt their energy metabolism to nutritional challenges or disease. To unravel the molecular basis of these adaptations, we generated a comprehensive proteome dataset of all major CNS cell types. Magnetic bead sorting was used to acutely isolate neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells from the cortex of individual young and adult mice challenged by feeding ketogenic diet or by neuroinflammatory disease. Label-free quantification of cell type-specific proteomes was performed by using an ion mobility-enhanced data-independent acquisition (DIA) workflow with alternating low and elevated energy (referred to as UDMSE). The combination of tissue metabolomic and expression analyses with cellular proteomic and transcriptomic analyses revealed that the strategies to manage the altered availability of energy metabolites differed between CNS cell types. Our data provide insights into key mechanisms of cell type-specific metabolic remodeling and a framework for the crosstalk between CNS cells in response to CNS challenges, which may have implications for the management of neurological diseases.