Within neurons, BHB and AcAc are metabolized to acetyl CoA, which then enters the tricarboxylic acid (TCA) cycle in mitochondria, resulting in the production of ATP and the reducing agents that transfer electrons to the electron transport chain. BHB and AcAc are transported from the blood into the brain and then into neurons via monocarboxylic acid transporters (MCTs) in the membranes of vascular endothelial cells and neurons. The FFAs are transported into hepatocytes, where they are metabolized via β-oxidation to acetyl CoA, which is then used to generate the ketones acetone, acetoacetate (AcAc) and β-hydroxybutyrate (BHB). Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.ĭuring fasting and sustained exercise, liver glycogen stores are depleted and lipolysis of triacylglycerols and diacylglycerols in adipocytes generates free fatty acids (FFAs), which are then released into the blood. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction.
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