Ingested ketone ester leads to a rapid rise of acetyl-CoA and competes with glucose metabolism in the brain of non-fasted mice

Laurent Suissa (1, 2, 3) , Pavel Kotchetkov (1, 3) , Jean-Marie Guigonis (1, 3) , Emilie Doche (2) , Ophélie Osman (2) , Thierry Pourcher (1, 3) , Sabine Lindenthal (1, 3)

1 TIRO-MATOs UMR E4320 - Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux
2 CHU Marseille
3 JOLIOT - Institut des Sciences du Vivant Frédéric JOLIOT

The role of ketone bodies in the cerebral energy homeostasis of neurological diseases has begun to attract recent attention particularly in acute neurological diseases. In ketogenic therapies, ketosis is achieved by either a ketogenic diet or by the administration of exogenous ketone bodies. The oral ingestion of the ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is a new method to generate rapid and significant ketosis (i.e., above 6 mmol/L) in humans. KE is hydrolyzed into β-hydroxybutyrate (βHB) and its precursor 1,3-butanediol. Here, we investigate the effect of oral KE administration (3 mg KE/g of body weight) on brain metabolism of non-fasted mice using liquid chromatography in tandem with mass spectrometry. Ketosis (Cmax = 6.83 ± 0.19 mmol/L) was obtained at Tmax = 30 min after oral KE-gavage. We found that βHB uptake into the brain strongly correlated with the plasma βHB concentration and was preferentially distributed in the neocortex. We showed for the first time that oral KE led to an increase of acetyl-CoA and citric cycle intermediates in the brain of non-fasted mice. Furthermore, we found that the increased level of acetyl-CoA inhibited glycolysis by a feedback mechanism and thus competed with glucose under physiological conditions. The brain pharmacodynamics of this oral KE strongly suggest that this agent should be considered for acute neurological diseases.

Mots clés: cerebral energy metabolism; exogenous ketone bodies; ketogenic diet; ketone ester; ketosis; β-hydroxybutyrate

Domaines: Sciences du Vivant [q-bio]

Laurent Suissa, Pavel Kotchetkov, Jean-Marie Guigonis, Emilie Doche, Ophélie Osman, et al.. Ingested ketone ester leads to a rapid rise of acetyl-CoA and competes with glucose metabolism in the brain of non-fasted mice. International Journal of Molecular Sciences, 2021, 22 (2), pp.524. ⟨10.3390/ijms22020524⟩. ⟨cea-03628022⟩