β‑Hydroxybutyrate Supports Energetically Demanding Neural Functions During Glucose Deprivation
In an ex‑vivo rat brain model, incubation with β‑hydroxybutyrate (BHB) as the sole exogenous fuel preserved mitochondrial respiration and allowed repeated spreading depolarizations, indicating that BHB can temporarily sustain high‑energy neural activity when glucose is unavailable.
Study and findings
The authors used isolated Sprague‑Dawley rat brain slices placed in artificial cerebrospinal fluid lacking glucose but enriched with β‑hydroxybutyrate. After a 4‑hour incubation, mitochondrial oxygen consumption was measured, and the tissue’s ability to recover from spreading depolarization—a severe, rapid energy challenge—was tested. Compared with slices incubated in glucose‑containing fluid, BHB‑incubated slices showed lower basal O₂ flux yet retained electron‑transfer system activity. Importantly, these slices could undergo multiple spreading depolarizations, whereas slices relying only on endogenous reserves failed after the first event. The authors interpret these data as evidence that exogenous BHB provides short‑term energetic support beyond endogenous substrates when glucose is absent.
Clinical interpretation
Although the work is preclinical, it demonstrates that ketone bodies can directly fuel neuronal mitochondria and sustain energetically intensive processes without concurrent glucose. This mechanistic insight aligns with the concept of cerebral fuel flexibility and suggests that, in contexts where glucose delivery is compromised—such as acute hypoglycemia or certain metabolic disorders—ketone supplementation might preserve neural function. However, the ex‑vivo setting does not replicate systemic metabolic regulation, and the short‑term nature of the experiment limits extrapolation to chronic clinical scenarios.
Limitations and open questions
The study employed isolated brain tissue from rats, which lacks vascular, hormonal, and whole‑body metabolic influences present in vivo. The duration of BHB support was limited to a few hours, leaving unanswered how sustained ketone availability would affect long‑term neuronal health or functional outcomes. Additionally, the concentration of BHB used was not compared with physiological levels achieved during fasting or ketogenic diets, and no dose‑response assessment was reported. Future investigations should address chronic exposure, translational relevance to human brain metabolism, and whether similar protective effects occur in intact organisms under pathological glucose deprivation.
Source
Ricks RL et al. β‑Hydroxybutyrate Maintains Energetically Demanding Neural Functions During Exogenous Glucose Deprivation. Cellular and Molecular Neurobiology. 2026.