Brain Ketone Bodies in Health, Evolution and Disease

Area of Science:

• Neuroscience
• Metabolic Biochemistry
• Epigenetics

Background:

• Ketone bodies (KBs) are the brain's primary energy source during fasting, increasing significantly in circulation.
• KBs activate their own cerebral utilization pathways, adapting brain metabolism to energy availability.
• Historically, KBs were vital for brain energy homeostasis during unpredictable food scarcity.

Purpose of the Study:

• To explore the dual role of ketone bodies as energy substrates and epigenetic regulators in the brain.
• To investigate the potential of manipulating KB levels for therapeutic interventions in neurodegenerative diseases.
• To understand why ketogenic diets (KDs) have not yet achieved widespread medical application despite their promise.

Main Methods:

• Review of physiological and molecular mechanisms of KB utilization and regulation in the brain.
• Analysis of KB's epigenetic modifications, such as lysine-butyrylation, on histone proteins.
• Discussion of the implications of KB's metabolic and epigenetic roles for fetal development and postnatal adaptation.

Main Results:

• Ketone bodies provide ATP and glutamate, activating their own cerebral transporters and enzymes.
• KBs act as epigenetic messengers, potentially mediating fetal adaptation to maternal starvation and retaining molecular memory of starvation.
• Circulating KB levels can be increased through nutritional interventions like ketogenic diets (KDs).

Conclusions:

• Ketone bodies possess unique transcriptional and epigenetic properties unmatched by other energy substrates.
• KBs offer therapeutic potential for neurodegenerative diseases with glucose hypometabolism, such as Alzheimer's disease.
• Further research is needed to overcome barriers hindering the clinical application of ketogenic diets.