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Recently, hyperketonemia induced by fasting or ketogenic diet calls attention because of the possibilities for various clinical applications. Animal species comparisons and biochemical data show that all fetuses can develop by using ketogenic energy through a pathway which seems to have been maintained. We hypothesized that 3-β-hydroxybutyrate (β-HB) could be the fuel for the basic engine that produces energy in all terrestrial species. However, ATP production from glucose-pyruvic acid pathway seems to be added as a dominant system in human. We hypothesize the establishment of TCA cycle in mitochondria and enough oxygen supply since two billion years ago would be the key events to promote this change. The efficacy of ATP production from β-oxidation product is 10 ATP molecules, while it is 12.5 molecules from pyruvic acid. So, evolution should select glucose burning system as a booster engine for energy production. The liver and kidney are major ketone producing organs which contain abundant glycogen particles. So, a close relationship between ketone and glucose burning system may be present. This explains why certain level of glucose is steadily maintained even in the hyperketogenic state. Ketogenic diets efficiently treat with gestational diabetes. Placenta is the ketogenic tissue which reflects high concentration of ketones in umbilical cord blood. In addition to the role of energy source, β-HB shows various pharmacological effects on disease prevention, such as cardiovascular disease, Alzheimer’s disease, epilepsy, etc. Inhibition of histone deacetylase, stimulation of FOXO, resistance to oxidative stress, protection of mitochondria, stimulation of adiponectin release, suppression of inflammasome, etc. are included. The contribution of intestinal microbiota to ketone body production should open a new field of medicine. Altogether, the above data suggest that longer-term human studies are necessary to exclude risks of unbalanced diet and to confirm the best combination of fuels for energy production, disease prevention and medical treatment.
Keywords: Ketone β-hydroxy butyrate; TCA cycle; Histon Gestational diabetes; Fast Endocrine; Metabolism Pharmacology; Ketone; β-hydroxy butyrate; Histon; Gestational diabetes; Fast; Endocrine; Metabolism; Pharmacology
The authors appreciate Dr. Philippe Culain, MSF, for his kind English revision and discussion.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflicts of interest.