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Ketone β-hydroxybutyrate restores memory and synapses during high-fat diet
Last reviewed: 09.08.2025
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Scientists from Spain, led by Dr. Roquio Rojas, published a large-scale study in Molecular Metabolism showing that β-hydroxybutyrate (BHB) completely blocks the neurodegenerative effects of a diet rich in saturated fats on synapses and cognitive function in mice.
Why is this important?
Diets high in palmitic acid (the main saturated fat in most animal fats and some vegetable oils) have long been linked to memory impairment and decreased synaptic plasticity. Meanwhile, BHB, a key ketone metabolite produced during fasting or a ketogenic diet, serves as an alternative energy source for neurons and is known for its anti-inflammatory and epigenetic effects.
Methods and experimental design
Cortical neuron culture
Mouse neurons were incubated with 200 µM palmitic acid, which resulted in a decrease in the density of AMPA GluA1 receptors on the membrane and inhibition of synaptic transmission.
In parallel, 5 mM BHB was added to the culture. The scientists found that BHB not only increased GluA1 expression on its own, but also completely neutralized the harmful effect of palmitate.
Hippocampal sections
Electrophysiological parameters of synapses were assessed in living brain slices. Palmitic acid reduced both amplitude and long-term potentiation (LTP), an indicator of synaptic plasticity. Introduction of BHB into the medium returned these parameters to the initial level.
Behavioural tests in animals
A group of mice were fed a diet containing 49 percent of their calories from saturated fat for two months. A control group ate a standard diet.
Memory was measured in the Maurice maze: a high-fat diet resulted in a deterioration in platform search time, whereas a daily oral dose of BHB (100 mg/kg) completely restored performance to the level of control animals.
Molecular mechanisms
- Energy Metabolism: BHB switches neurons from a glucose-dependent to a ketone-dependent pathway for producing ATP, reducing excess formation of reactive oxygen species during fat utilization.
- Anti-inflammatory effect: BHB inhibits NLRP3 inflammasome activation, reducing the release of proinflammatory cytokines and protecting neurons from secondary inflammatory damage.
- Epigenetic regulation: BHB acts as a natural inhibitor of histone deacetylases (HDAC), which leads to increased acetylation of histone proteins and increased transcription of genes responsible for synaptic remodeling and neuroprotection.
Prospects for clinical application
The authors emphasize that BHB may be a promising neuroprotector for people on unhealthy diets or suffering from obesity and metabolic syndrome. Further studies should determine:
- Optimal Dosages and Administration of BHB in Humans
- Duration and safety of intake - to avoid ketotic stress in patients with cardiovascular or renal pathologies.
- Possibility of synthesizing stable BHB analogues with improved bioavailability.
“Our work demonstrates that BHB not only compensates for energy deficits, but also directly restores key synaptic transmission molecules, protecting memory from fat damage,” concludes Dr. Rojas.
This research opens the door to new nutraceuticals and drugs that may protect the brain in the face of a modern diet rich in saturated fats and slow cognitive decline.