ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 240, No. 1, July, pp. 426-434, 1985 Regulation of Succinyl-CoA:3-Oxoacid CoA-Transferase in Developing Rat Brain: Responsiveness Associated with Prenatal but Not Postnatal Hyperketonemia PETER M. HANEY’ AND MULCHAND S. PATEL’ Departments of Biochemistry and Nutrition, Case Western Reserve University, Cleveland, Ohio &lo6 Received January 14, 1985, and in revised form February 27, 1985 Activities of ketone body-metabolizing enzymes in rat brain rise 3- to &fold during the suckling period, then fall more than 50% after weaning. Our purpose was to determine the mechanism of the developmental changes in activity of 3-oxoacid CoA- transferase in rat brain and to study its regulation by dietary modification. Purified rat brain 3-oxoacid CoA-transferase was used to generate specific antibody. Immu- notitrations of the enzyme from brains of 4-, 24-, and go-day-old rats indicated that changes in 3-oxoacid CoA-transferase activity during development are due to changes in content of the enzyme protein. Pulse-labeling studies showed that changes in enzyme specific activity reflected changes in its relative rate of synthesis, which increased 2.5fold between the nineteenth day of gestation and the third postnatal day, remained at this high level until the twelfth postnatal day, and declined thereafter, returning by Day 38 to the level observed in utero. The enzyme is apparently degraded very slowly during early postnatal life. Fetal hyperketonemia induced by feeding pregnant rats a high-fat diet was associated with an increase in the relative rate of synthesis of 3-oxoacid CoA-transferase in brains of 19-day-old fetuses and newborn rats and with an increase in the specific activity of the enzyme at birth. To examine the role of postnatal hyperketonemia in the development of the enzyme in brains of suckling rats, neonates received intragastric cannulas and were fed, for up to 13 days, a modified milk formula low in fat. Postnatal hyperketonemia was abolished but cerebral 3-oxoacid CoA-transferase specific activity on Days 10 and 17 was not significantly affected. Thus, the physiological hyperketonemia caused by the high fat content of rat milk is not required for the normal development of 3- oxoacid CoA-transferase in rat brain. 0 1985 Academic Press, Inc. Since Owen et al. (1) demonstrated that ketone bodies serve as primary energy substrates of adult human brain during prolonged starvation, the metabolism of these compounds by mammalian brain [for reviews see Refs. (2, 3)] and by neural cells in culture (4, 5) has been studied extensively. Acetoacetate and D-3-hy- droxybutyrate are important substrates for both energy metabolism and lipid bio- ’ Predoctoral Fellow supported by NIH Metabolism Training Grant AM 07319. *To whom correspondence should be addressed. synthesis in the developing rat brain (2, 3). The enzymes of ketone body metabo- lism, D-3-hydroxybutyrate dehydrogenase, succinyl-CoA:3-oxoacid CoA-transferase (3-oxoacid CoA-transferase), and aceto- acetyl-CoA thiolase, share a postnatal de- velopmental pattern unique among mito- chondrial enzymes of rat brain. The activ- ities of other mitochondrial enzymes, including several tricarboxylic acid cycle enzymes as well as aspartate and alanine aminotransferases, are very low in rat brain at birth, gradually attain adult ac- tivity by the end of the third postnatal 0003-9861/85 $3.00 Copyright 0 1985 by Academic Press, Inc. All rights of reproduction in any form reserved. 426