Regulatory Aspects of Glucose and Ketone Body Metabolism in Infant Rat Brain

Abstract

Summary: The present study was designed to investigate some of the possible factors responsible for the low rate of the oxidative use of glucose observed in neonatal rat brain. An evaluation of the role of pyruvate dehydrogenase (PDH, EC 1.2.4.1) showed that at all stages of brain development, the activities of both molecular forms of this enzyme are considerably less than those reported for the enzymes localized above in the glycolytic pathway. The proportion of both molecular forms is not altered during brain maturation. The activities of the active form and of the total enzyme in adult brain are 0.56 and 1.1 μmole/min/g brain, respectively. It is concluded that PDH represents the rate-limiting step in the oxidation of glucose by neonatal brain due to a delay in the synthesis of the enzyme protein. A “cross-over” plot of glycolytic intermediates in neonatal brain showed that only fructose 1,6-bisphosphate concentrations are significantly lower than in adult brain, indicating a block at the level of phosphofructokinase (PFK, EC 2.7.1.11). A marked increase in citrate concentrations in neonatal brain (values ranging from 0.44–0.82 μmole/g brain) with regard to adult levels (0.28 μmol/g brain) is suggested to be responsible for the inhibition of the enzyme. Glucose 6-phosphate concentrations in neonatal brain are not different from adult values. Despite increasing ketonemia neither consistent intracerebral accumulation of glucose nor a decrease in the brain/blood ratio of glucose is observed during brain maturation. These data argue against limitations of glucose use at the level of hexokinase or membrane transport in the neonatal brain. Speculation: Ketone bodies are major substrates of the neonatal brain in that they fulfill to a large extent both the energy requirements of the brain and provide carbon for the needs of biosynthetic processes. The dual function of ketone bodies cannot be substituted for alternatively by glucose due to a limitation in the oxidative breakdown of glucose observed in young rat brain. Thus, glucose is saved for preferential use in the pentosephosphate pathway, providing hydrogen equivalents for the synthesis of myelin lipids, a process which is very active in neonatal brain.