Acetoacetate metabolism in infant and adult rat brain in vitro

Abstract

1. Acetoacetate or dl-β-hydroxybutyrate increases the rate of oxygen consumption to a smaller extent than that brought about by glucose or pyruvate in adult rat brain-cortex slices but to the same extent as that in infant rat brain-cortex slices. 2. The rate of ¹⁴CO₂ evolution from [1-¹⁴C]glucose considerably exceeds that from [6-¹⁴C]glucose in respiring infant rat brain-cortex slices, in contrast with adult brain-cortex slices, suggesting that the hexose monophosphate shunt operates at a greater rate in the infant rat brain than in the adult rat brain. 3. The rate of ¹⁴CO₂ evolution from [3-¹⁴C]acetoacetate or dl-β-hydroxy[3-¹⁴C]butyrate, in the absence of glucose, is the same in infant rat brain slices as in adult rat brain slices. It exceeds that from [2-¹⁴C]glucose in infant rat brain but is less than that from [2-¹⁴C]glucose in adult rat brain. 4. Acetoacetate is oxidized in the brain through the operation of the citric acid cycle, as shown by the accelerating effect of glucose on acetoacetate oxidation in adult brain slices, by the inhibitory effects of malonate in both infant and adult brain slices and by its conversion into glutamate and related amino acids in both tissues. 5. Acetoacetate does not affect glucose utilization in adult or infant brain slices. It inhibits the rate of ¹⁴CO₂ formation from [2-¹⁴C]glucose or [U-¹⁴C]-glucose the effect not being wholly due to isotopic dilution. 6. Acetoacetate inhibits non-competitively the oxidation of [1-¹⁴C]pyruvate, the effect being attributed to competition between acetyl-CoA and CoA for the pyruvate-oxidation system. 7. Acetoacetate increases the rate of aerobic formation of lactate from glucose with both adult and infant rat brain slices. 8. The presence of 0.1mm-2,4-dinitrophenol diminishes but does not abolish the rate of ¹⁴CO₂ formation from [3-¹⁴C]acetoacetate in rat brain slices. This points to the participation of ATP in the process of oxidation of acetoacetate in infant or adult rat brain. 9. The presence of 5mm-d-glutamate inhibits the rate of ¹⁴CO₂ formation from [3-¹⁴C]acetoacetate, in the presence or absence of glucose. 10. Labelled amino acids are formed from [3-¹⁴C]acetoacetate in both adult and infant rat brain-cortex slices, but the amounts are smaller than those found with [2-¹⁴C]glucose in adult rat brain and greater than those found with [2-¹⁴C]glucose in infant rat brain. 11. Acetoacetate is not as effective as glucose as a precursor of acetylcholine in adult rat brain but is as effective as glucose in infant rat brain slices. 12. Acetoacetate or β-hydroxybutyrate is a more potent source of acetyl-CoA than is glucose in infant rat brain slices but is less so in adult rat brain slices.