Ketones suppress brain glucose consumption
Neurodegeneration after oxidative stress limits the recovery of tissue response and appears to be caused by impaired glycolysis. If indeed there is a defect in glucose metabolism it might be beneficial to supplement energy metabolism with an alternate substrate. It was suggested that brain can supplement glucose as the principal energy substrate with ketone bodies1–3 without altering oxygen consumption4,5.
Classic studies of ketosis induced by fasting or starvation in humans showed that brain function was maintained which was attributed to the utilization (oxidation) of ketone bodies as alternate energy substrates to glucose by the brain6. Rats that have been fasted for 2–3 days showed no difference in cerebral blood flow (CBF) or CMRO27.
One mechanism by which ketosis might be beneficial is through the metabolic step where ketones enter the TCA cycle at the level of citrate bypassing glycolysis, the step after pyruvate dehydrogenase complex where the enzyme activity is often impaired. Through feed-back regulation, ketones are known to down regulate glycolytic rates at various levels such as citrate, phosphofructokinase and/or hexokinase.
In addition, particularly in brain, ketones are a carbon source for glutamate (anaplerosis) and thus help to balance glutamate/glutamine homeostasis through stabilization of energy metabolism in astrocyte following recovery from a hypoxic/ischemic event.
Based on our experiments and evidence in the literature, we have developed the hypothesis that ketones are effective against pathology associated with altered glucose metabolism, the rationale being that ketosis helps to regulate glucose metabolism. In this study, the effects of ketosis on the local cerebral metabolic rate of glucose consumption (CMRglu) were investigated in an in vivo rat model of ketosis using positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (FDG).