D-ꞵ-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.
Bartosz KulaBotond AntalCorey WeistuchFlorian GackièreAlexander BarreVictor VeladoJeffrey M HubbardMaria KukleyLilianne Rivka Mujica-ParodiNathan Anthony SmithPublished in: PNAS nexus (2024)
The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability 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 exogenous KB D-ꞵ-hydroxybutyrate (D-ꞵHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ꞵHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential properties, while D-ꞵHb rescued neuronal functions associated with axonal conduction, synchronization, and LTP.
Keyphrases
- cerebral ischemia
- insulin resistance
- liver failure
- type diabetes
- subarachnoid hemorrhage
- respiratory failure
- spinal cord injury
- blood brain barrier
- metabolic syndrome
- high fat diet
- brain injury
- polycystic ovary syndrome
- blood glucose
- skeletal muscle
- glycemic control
- protein kinase
- blood pressure
- white matter
- risk assessment
- climate change
- human health
- functional connectivity
- mechanical ventilation