1.The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KB) during low glucose availability. Neuronal KB uptake, which does not rely on the glucose transporter 4 (GLUT4) and insulin, has shown promising clinical applications in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of the exogenous KB D-β-hydroxybutyrate (D-βHb) on mouse brain metabolism during acute insulin resistance (AIR). We found the impacts of AIR and D-βHb to be qualitatively distinct across neuronal compartments: AIR decreased synaptic activity and LTP, and impaired axonal conduction, synchronization, and action potential (AP) properties. D-βHb rescued neuronal functions connected to axonal conduction and synchronization but did not rescue synaptic activity. While DβHb failed to rescue synaptic activity, it successfully rescued neuronal functions associated with axonal conduction and synchronization.

10.Competing Interests All authors declare no competing interest.