[2,4-13 C2 ]-beta-Hydroxybutyrate metabolism in human brain

Abstract

Infusions of [2,4-13C2]-beta-hydroxybutyrate and 1H-13C polarization transfer spectroscopy were used in normal human subjects to detect the entry and metabolism of beta-hydroxybutyrate in the brain. During the 2-hour infusion study, 13C label was detectable in the beta-hydroxybutyrate resonance positions and in the amino acid pools of glutamate, glutamine, and aspartate. With a plasma concentration of 2.25 +/- 0.24 mmol/L (four volunteers), the apparent tissue beta-hydroxybutyrate concentration reached 0.18 +/- 0.06 mmol/L during the last 20 minutes of the study. The relative fractional enrichment of 13C-4-glutamate labeling was 6.78 +/- 1.71%, whereas 13C-4-glutamine was 5.68 +/- 1.84%. Steady-state modeling of the 13C label distribution in glutamate and glutamine suggests that, under these conditions, the consumption of the beta-hydroxybutyrate is predominantly neuronal, used at a rate of 0.032 +/- 0.009 mmol. kg-1. min-1, and accounts for 6.4 +/- 1.6% of total acetyl coenzyme A oxidation. These results are consistent with minimal accumulation of cerebral ketones with rapid utilization, implying blood-brain barrier control of ketone oxidation in the nonfasted adult human brain.

FIG. 1

¹³C spectrum, acquired from subject 2 during the 60- to 120-minute period in the infusion study. For processing parameters, see text.

FIG. 2

(A) Time course of brain (closed symbols) BHB in millimolar concentration. Open symbols are plasma BHB concentrations multiplied by 0.10. Data are from volunteer 4. The gradual increase in plasma BHB seen in this volunteer after plasma levels reached greater than 2 mmol/L was typical (see text). (B) Time course of the relative fractional enrichment of Glu4 (filled diamonds), Gln4 (open diamonds) and Asp3 (triangles) from volunteer 4.

FIG. 3

¹³C spectra, acquired from infusions of BHB (A, bottom), glucose (B, middle), and acetate (C, top). The BHB spectrum was acquired during the 60- to 120-minute period in the infusion study (volunteer 2). For comparison between the three spectra, the BHB spectrum was processed using a Gaussian broadening of 1.8Hz. For processing parameters, see text. (B) ¹³C spectrum acquired during the 120- to 160-min period in a ¹³C-glucose infusion study, reproduced from Shen et al. (1999) (C) ¹³C spectrum acquired during the 120- to 160-minute period in a ¹³C-acetate infusion study.

FIG. 4

Metabolic model for BHB oxidation (A) showing flow in neurons and astrocytes. To distinguish between ketone flow from neuronal and astrocytic metabolism, the fluxes resulting from neuronal intake are shown in thick black; the fluxes resulting from astrocytic intake are in gray. (B) Model including flow into aspartate. KB, ketone body; Pyr/Lac, pyruvate + lactate; OAA, oxaloacetate; α-kg, α-ketoglutarate; Gln, glutamine; Glu, glutamate; Asp, aspartate; V_kb, oxidative flux of ketones either neuronal or astrocytic; V_tca, TCA-cycle rate flowing into α-kg, either neuronal or astrocytic; V_ox, TCA-cycle rate flowing out of α-kg, either neuronal or astrocytic; V_cyc, cycling rate between neuronal and astrocytic Glu; V_gs, glutamine synthesis rate; V_ret, return of astrocytic glutamine to neuronal glutamate; V_gln, neuronal glutaminase rate; V_eff, rate of loss of glutamine.