Dr. Nora Volkow, of NIDA, observed that alcohol consumption decreased brain glucose utilization in alcoholic subjects in a pattern which resemble GABAergic stimulation. Dr. T-K Li pointed out that the decrease in glucose utilization could be explained by the brain metabolism of acetate, which reaches blood levels of 2 mM during ethanol metabolism. In collaboration with Dr. George Kunos and members of the Lab of Physiological Studies, we determined that brain uptake of F dexoyglucose was significantly decreased by elevation of blood acetate to 5 or 2 mM acetate, the Km for acetate transport into brain being about 5 mM. Simple measurement of a decreased rate of glucose utilization provides little information on the effects of switching from glucose to acetate metabolism on brain energetics, neurotransmitter, transcription or neuropeptide metabolism. While the effects of ethanol on brain and liver function have been extensively studied by the NIAAA and others for many years, there has been relatively little attention paid to the effects of acetate on the energy metabolism in brain. Opening of the mitochondrial permeability transition pore, destroys the proton gradient upon which the synthesis of ATP depends. It therefore is essentially uncoupling of the transport to electrons in the respiratory chain from the synthesis of ATP, in essence acting as an uncoupling agent such as FCCP. Prolonged opening of the pore allows for movement of larger molecules such as cytochrome C out of mitochondria into cytoplasm triggering the process of apoptosis. In our studies, we found that the administration of ethanol or acetate to the rat, led to a decrease in the phosphorylation of glucose by brain. We also found that administration of acetate lead to a decrease in the delta G'of ATP hydrolysis. We have now shown that the metabolism of acetate by brain causes significant changes in brain physiology, namely a decrease in glucose phosphorylation, a decrease in the delta G'of ATP hydrolysis, oxidation of the mitochondrial NAD and Q couples, reduction of the cytosolic NAD couple indicative of uncoupling of oxidation phosphorylation. Because of the profound changes on brain physiology, a further study of the conditions which must pertain to cause these changes in the course of normal ethanol consumption is warranted. It is proposed that this phenomena be explored further in a collaborative study with Prof Britton Chance of the University of Pennsylvania, where the amount of heat produced by the opening to the mitochondrial voltage dependent pore is measured after opening by acetate.
|Pawlosky, Robert J; Kashiwaya, Yoshihiro; Srivastava, Shireesh et al. (2010) Alterations in brain glucose utilization accompanying elevations in blood ethanol and acetate concentrations in the rat. Alcohol Clin Exp Res 34:375-81|
|Kashiwaya, Yoshihiro; Pawlosky, Robert; Markis, William et al. (2010) A ketone ester diet increases brain malonyl-CoA and Uncoupling proteins 4 and 5 while decreasing food intake in the normal Wistar Rat. J Biol Chem 285:25950-6|
|Bergman, Christian; Kashiwaya, Yoshihiro; Veech, Richard L (2010) The effect of pH and free Mg2+ on ATP linked enzymes and the calculation of Gibbs free energy of ATP hydrolysis. J Phys Chem B 114:16137-46|