[2,4-¹³C₂]-β-Hydroxybutyrate Metabolism in Human Brain

Abstract

SummaryInfusions of [2,[4][5][6][7][8][9][10][11][12][13] C 2 ]-β-hydroxybutyrate and 1 H-13 C polarization transfer spectroscopy were used in normal human subjects to detect the entry and metabolism of β-hydroxybutyrate in the brain. During the 2-hour infusion study, 13 C label was detectable in the β-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 β-hydroxybutyrate concentration reached 0.18 ± 0.06 mmol/L during the last 20 minutes of the study. The relative fractional enrichment of 13 C-4-glutamate labeling was 6.78 ± 1.71%, whereas 13 C-4-glutamine was 5.68 ± 1.84%. Steady-state modeling of the 13 C label distribution in glutamate and glutamine suggests that, under these conditions, the consumption of the β-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. KeywordsKetones; Magnetic resonance spectroscopy; 13 C; β-Hydroxybutyrate; Glutamate; Metabolism Although glucose is the predominant fuel for the mammalian brain, it is well known that ketones can also be readily utilized, particularly under situations of fasting, strenuous exercise, or particular diets (Robinson and Williamson, 1980). In rodents, the measurement of the ketone contribution towards brain metabolism has typically been performed through extract or autoradiographic studies of radioactive tracers (Cremer, 1971;Nehlig et al., 1991). In studies of lightly anesthetized rodents, brain ketone consumption has been reported to be small, at approximately 3% of total (Hawkins et al., 1986). This contrasts to measurements made in humans, performed through [ 11 C]-β-hydroxybutyrate (BHB) positron emission tomography (PET) (Blomqvist et al., 1995) and AV difference measurements (Owen et al., 1965;Hasselbalch et al., 1994Hasselbalch et al., , 1996. In fasted and nonfasted human studies, ketones have been reported to provide a substantially larger fraction of brain oxidative metabolism, up to 50% of energy production in 3-week fasted obese subjects. The basis for these differences may have a variety of causes, including level of anesthesia, species differences, and physiologic state. In particular, entry of ketones has been shown by several investigators to be induced with fasting (Gjedde and Crone, 1975;Pollay and Stevens, 1980 Human brain metabolism may be also studied by carbon 13 ( 13 C) magnetic resonance (MR) spectroscopy. The 13 C nucleus is a stable isotope of carbon, which is nuclear magnetic resonance (NMR) detectable, and is naturally present at 1.1% abundance. The level of 13 C in brain metabolite pools may be measured regionally and noninvasively by localized 13 C or 1 H-13 C MR spectroscopy. As has b...

Global Cerebral Blood Flow and Metabolism during Acute Hyperketonemia in the Awake and Anesthetized Rat

“…The b-hydroxybutyrate infusion therefore caused a resetting between the CBF and the cerebral metabolism of oxygen and glucose. We observed no decrease in glucose metabolism and no substitution of glucose by ketone bodies for the oxidative metabolism, as has been shown in humans both during short-term fasting (Hasselbalch et al, 1994) as well as during ketone body infusion (Hasselbalch et al, 1996;Pan et al, 2002), indicating a possible species difference. The arteriovenous differences for b-hydroxybutyrate during infusion of b-hydroxybutyrate were negligible -0.02 mmol/ L (s.d.…”

Cortical Substrate Oxidation during Hyperketonemia in the Fasted Anesthetized Rat in Vivo

“…The dynamic enrichment pattern is nearly identical to that observed when [1-13 C]glucose is the infused substrate (e.g., see the study by Pan et al (2002)). In addition to the enriched amino acids, 13 C-labeled acetone was also observed during 13 C-BHB infusion ( Figure 3B; Supplementary Figure S1A), a product not observed during infusions of other substrates, such as [1,6-13 C 2 ]glucose or [2-13 C]acetate (Supplementary Figure S1B and C).…”

“…Increased astroglial acetate metabolism has been observed in mice maintained on a ketogenic diet possibly reflecting adaptation to prolonged ketonemia (Melo et al, 2006;Yudkoff et al, 2005). In contrast, a study of acute hyperketonemia in overnight-fasted humans (Pan et al, 2001(Pan et al, , 2002 infused intravenously with [2,4-13 C 2 ]-D-BHB revealed a pattern of brain glutamate and glutamine labeling similar to that from [1-13 C]glucose, indicating that oxidation of BHB, like glucose, occurred mostly in neurons-conclusions in line with results of early 14 C-labeled BHB tracer studies (Hawkins et al, 1986). Although brain utilization of ketone bodies is increased by fasting, contradictory findings have appeared on the effects of ketone bodies on brain glucose consumption.…”

Neuroprotective and disease-modifying effects of the ketogenic diet

“…These fats are converted to the ketone bodies β-hydroxybutyrate, acetoacetate, and acetone, which represent an alternative energy source to glucose. In comparison with glucose, ketone bodies have a higher inherent energy (Pan et al, 2002;Cahill and Veech, 2003). In adults, glucose is the preferred substrate for energy production, particularly by the brain.…”

“…In addition, ketone bodies, especially acetoacetate, are preferred substrates for the synthesis of neural lipids. Ketone bodies readily cross the blood-brain barrier either by simple diffusion (acetone) or with the aid of monocarboxylic transporters (β-hydroxybutyrate, acetoacetate), whose expression is related to the level of ketosis (Pan et al, 2002;Pierre and Pellerin, 2005).…”