Chronic ketosis and cerebral metabolism

Abstract

The effects of chronic ketosis on cerebral metabolism were determined in adult rats maintained on a high-fat diet for approximately three weeks and compared to a control group of animals. The fat-fed rats had statistically significantly lower blood glucose concentrations and higher blood beta-hydroxybutyrate and acetoacetate concentrations; higher brain concentrations of bound glucose, glucose 6-phosphate, pyruvate, lactate, beta-hydroxybutyrate, citrate, alpha-ketoglutarate, alanine, and adenosine triphosphate (ATP); lower brain concentrations of fructose 1,6-diphosphate, aspartate, adenosine diphosphate (ADP), creatine, cyclic nucleotides, succinyl coenzyme A (CoA), acid-insoluble CoA, and total CoA; and similar brain concentrations of glucose, malate, calculated oxaloacetate, glutamate, glutamine, adenosine monophosphate, phosphocreatine, reduced CoA, acetyl CoA, sodium, potassium, chloride, and water content. The metabolite data in the chronically ketotic rats demonstrate an increase in the cerebral energy reserve and energy charge. These data also suggest negative modification of the enzymes phosphofructokinase, pyruvic dehydrogenase, and alpha-ketoglutaric dehydrogenase; positive modification of glycogen synthase; and possible augmentation of the hexose transport system. There was no demonstrable difference in brain pH, water content, or electrolytes in the two groups of animals. We speculate that the increased brain ATP/ADP ratio is central to most, if not all, the observed metabolic perturbations and may account for the increased neuronal stability that accompanies chronic ketosis.

Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening KATPChannels

“…Early studies on the ketogenic diet in rodents (Appleton and DeVivo, 1974;DeVivo et al, 1978) found that in whole-brain extracts, the levels of substrates in the glycolytic pathway are altered, consistent with reduced utilization of glucose for energy. This fits with the classical understanding of the regulation of glycolysis.…”

“…Inhibition of glycolysis by the ketogenic diet was found in the early biochemical work of DeVivo et al (1978). The importance of glycolytic inhibition in the mechanism of the diet is supported by the success of caloric restriction studies in animals (Greene et al, 2001) and by the success of a modified dietary therapy in humans, the Low Glycemic Index Treatment .…”

The Neuropharmacology of the Ketogenic Diet

“…In the presence of plentiful acetyl-CoA from fat metabolism, the first segments of the Krebs cycle are highly active, producing an abundance of α-ketoglutarate, the levels of which have been observed to be increased in an adult rat ketogenic diet model [37]. The equilibrium of the transamination reaction toward oxaloacetate in the presence of increased α-ketoglutarate implies that availability of glutamate will be enhanced.…”

“…It seems plausible that the greater energy reserve would enhance the capacity of neurons to withstand metabolic challenges and could account for the ability of the diet to confer neuroprotection in models of neurodegenerative diseases or stroke [5]. It also has been proposed that effects of the ketogenic diet on brain energetics contribute to the seizure protection conferred by the diet [37,42], although there is little experimental support for this concept.…”

Ketogenic Diet: Effects on Expression of Kindled Seizures and Behavior in Adult Rats

“…The anticonvulsant effect of the KD has been proposed to be related to the brain's transition from carbohydrates to fats (ketone bodies) as its primary energy source (39). The switch to ketones for energy may cause a long-term adaptation in the brain's energy metabolism.…”