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
- spinal cord injury
- respiratory failure
- adipose tissue
- metabolic syndrome
- blood brain barrier
- brain injury
- high fat diet
- blood glucose
- drug induced
- glycemic control
- oxidative stress
- physical activity
- high fat diet induced
- resting state
- white matter
- hepatitis b virus
- risk assessment
- weight loss
- acute respiratory distress syndrome