Fetal fuels. IV. Regulation of branched-chain amino and keto acid metabolism in fetal brain

Abstract

The regulation of branched-chain amino and keto acid metabolism was examined in fetal rat brains at 20 days gestation. When fetal brain slices were incubated with [1-14C]leucine, graded concentrations of beta-hydroxybutyrate or acetoacetate resulted in a progressive rise in labeled alpha-ketoisocaproic acid accompanied by a fall in 14CO2, whereas the sum of these products remained unchanged. These reciprocal relationships were maintained when leucine concentrations were varied from 0.4 to 4 mM. Increasing concentrations of glucose or pyruvate enhanced the formation of both 14CO2 and alpha-ketoisocaproic acid from [1–14C]leucine, but resulted in a progressive decrease in the conversion of alpha-ketoisocaproic acid to 14CO2. That glucose and ketone bodies probably acted via separate mechanisms was suggested by a further inhibition of alpha-ketoisocaproic acid decarboxylation whenever beta-hydroxybutyrate was added. When mothers were starved from days 18–20, a threefold rise in circulating branched-chain keto acids was reflected concordantly in the fetus and was attended by a significant enhancement of leucine transaminase activity in fetal brain. Because levels of circulating ketone bodies reported during maternal starvation were maximally effective in diminishing the conversion of alpha-ketoisocaproic acid to 14CO4, it is suggested that the inhibitory effects of beta-hydroxybutyrate on the critical dehydrogenase step in branched-chain keto acid metabolism in fetal brain could restrain oxidation of maternally derived alpha-ketoisocaproic acid, thereby permitting salvage for reversible transamination to leucine.