The Rate of Cerebral Utilization of Glucose, Ketone Bodies, and Oxygen: A Comparative in Vivo Study of Infant and Adult Rats

Dahlquist, G; Persson, Bengt

doi:10.1203/00006450-197611000-00002

Cited by 74 publications

(60 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to awake rats, studies of barbiturate anesthetized and hyperketonemic (48-hour fast) adult rats consistently found higher ketone body contributions to total brain substrate oxidation, with values of 18% and 29% of total oxidation for [BHB] plasma of 0.64 mM and 2 mM, respectively. 28,29 In a study that compared 24-hour and 48-hour fasted rats under PB anesthesia, including an acute infusion of DL-BHB in 24-hour fasted rats ([BHB] plasma ¼ 0.83, 2.05, and 5.52 mM, respectively), Ruderman et al 30 found that ketone bodies accounted for 28%, 33%, and 68% respectively of total acetyl-CoA oxidation. For the halothaneanesthetized rats in the present study ([BHB] plasma ¼ 6.6 mM), 48% of acetyl-CoA oxidation was fueled by ketone bodies, which is in reasonable agreement with the above studies.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

Chowdhury

Jiang

Rothman

et al. 2014

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

The capacity of ketone bodies to replace glucose in support of neuronal function is unresolved. Here, we determined the contributions of glucose and ketone bodies to neocortical oxidative metabolism over a large range of brain activity in rats fasted 36 hours and infused intravenously with [2,4-13 C 2 ]-D-b-hydroxybutyrate (BHB). Three animal groups and conditions were studied: awake ex vivo, pentobarbital-induced isoelectricity ex vivo, and halothane-anesthetized in vivo, the latter data reanalyzed from a recent study. Rates of neuronal acetyl-CoA oxidation from ketone bodies (V acCoA-kbN ) and pyruvate (V pdhN ), and the glutamateglutamine cycle (V cyc ) were determined by metabolic modeling of 13 C label trapped in major brain amino acid pools. V acCoA-kbN increased gradually with increasing activity, as compared with the steeper change in tricarboxylic acid (TCA) cycle rate (V tcaN ), supporting a decreasing percentage of neuronal ketone oxidation: B100% (isoelectricity), 56% (halothane anesthesia), 36% (awake) with the BHB plasma levels achieved in our experiments (6 to 13 mM). In awake animals ketone oxidation reached saturation for blood levels 417 mM, accounting for 62% of neuronal substrate oxidation, the remainder (38%) provided by glucose. We conclude that ketone bodies present at sufficient concentration to saturate metabolism provides full support of basal (housekeeping) energy needs and up to approximately half of the activity-dependent oxidative needs of neurons. Keywords: 13 C isotopes; glucose utilization; glutamate/glutamine cycle; ketone body utilization; neuroenergetics; nuclear magnetic resonance spectroscopy INTRODUCTIONThe adult mammalian brain shows a remarkably high utilization of glucose compared with other potential fuel substrates, such as lactate or ketone bodies. Brain consumption of alternate substrates is limited by transport from the blood, and factors which alter membrane transport alter the rate of consumption. Under fasting conditions, starvation, or diets high in fats, blood ketone body levels rise, increasing their cerebral rate of consumption. The extent to which ketone bodies can support the different aspects of brain function, once transport is no longer limiting, has not been clearly established. Ketone bodies are metabolized by neurons and astrocytes in vitro and in vivo, 1-3 and like glucose, neuronal (glutamatergic) oxidation dominates quantitatively in vivo, 3,4 reflecting the relatively larger volume fraction of neurons compared with glial cells. Despite extensive study to ascertain the role of ketone bodies in neural function, basic unanswered questions persist about their involvement, and that of glucose, in the energy requirements associated with neurotransmission.Previous studies from our laboratory using 13 C magnetic resonance spectroscopy (MRS) with [1-13 C]glucose reported a linear relationship between neuronal oxidation of glucose in the tricarboxylic acid (TCA) cycle and glutamate (Glu)-glutamine (Gln) cycling flux over a large range of brain activity, 5-7...

show abstract

Section: Discussionmentioning

confidence: 99%

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

Chowdhury

Jiang

Rothman

et al. 2014

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…However, upon increasing bHB arterial concentrations by starvation for 2 days or more, cerebral uptake is significantly enhanced (Hawkins et al 1971). Increased cerebral uptake of bHB has also been shown during development (Hawkins et al 1971;Dahlquist and Persson 1976), following starvation (Owen et al 1967) and in diabetes (Kries and Ross 1992). The brain's ability to increase its reliance on bHB appears to be a common form of cerebral metabolic adaptation under conditions of insufficient glucose availability and developmental increases in cerebral energy demand.…”

mentioning

confidence: 99%

“…In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al 1986a) (Edmond et al 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al 1967;Hawkins et al 1971;Dahlquist and Persson 1976). In normally fed adult mammals bHB metabolism comprises less than 3% of total cerebral metabolism and bHB is present in low circulating concentrations (0.1 mM) with negligible uptake into the brain (Hawkins et al 1971).…”

Section: Introductionmentioning

confidence: 99%

“…Keywords: alternative substrates, b-hydroxybutyrate, metabolism, traumatic brain injury. Although glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts to alternative substrates (Owen et al 1967;Hawkins et al 1971;Dahlquist and Persson 1976;Kries and Ross 1992;Vannucci and Vannucci 2000). In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al 1986a) (Edmond et al 1987).…”

mentioning

confidence: 99%

“…Although glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts to alternative substrates (Owen et al 1967;Hawkins et al 1971;Dahlquist and Persson 1976;Kries and Ross 1992;Vannucci and Vannucci 2000). In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al 1986a), lactate (Brandt et al 1984;McKenna et al 1994), glutamine/glutamate (Yu et al 1984;McKenna et al 1994), citrate (Westergaard et al 1994), malate (McKenna et al 1994(McKenna et al , 1990, b-hydroxybutyrate (bHB) (Edmond et al 1987;McKenna et al 1994), acetoacetate (Lopes-Cardozo et al 1986;Waniewski and Martin 1998), as well as octanoate and palmitate (Edmond et al 1987).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Prins

Lee

Fujima

et al. 2004

Journal of Neurochemistry

101

View full text Add to dashboard Cite

There is growing evidence of the brain's ability to increase its reliance on alternative metabolic substrates under conditions of energy stress such as starvation, hypoxia and ischemia. We hypothesized that following traumatic brain injury (TBI), which results in immediate changes in energy metabolism, the adult brain increases uptake and oxidation of the alternative substrate b-hydroxybutyrate (bHB). Arterio-venous differences were used to determine global cerebral uptake of bHB and production of 14 CO 2 from [ 14 C]3-bHB 3 h after controlled cortical impact (CCI) injury. Quantitative bioluminescence was used to assess regional changes in ATP concentration. As expected, adult sham and CCI animals with only endogenously available bHB showed no significant increase in cerebral uptake of bHB or 14 CO 2 production. Increasing arterial bHB concentrations 2.9-fold with 3 h of bHB infusion failed to increase cerebral uptake of bHB or 14 CO 2 production in adult sham animals. Only CCI animals that received a 3-h bHB infusion showed an 8.5-fold increase in cerebral uptake of bHB and greater than 10.7-fold increase in 14 CO 2 production relative to sham bHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of bHB infusion beginning immediately after CCI injury. Keywords: alternative substrates, b-hydroxybutyrate, metabolism, traumatic brain injury. Although glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts to alternative substrates (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976;Kries and Ross 1992;Vannucci and Vannucci 2000). In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al. 1986a) (Edmond et al. 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976). In normally fed adult mammals bHB metabolism comprises less than 3% of total cerebral metabolism and bHB is present in low circulating concentrations (0.1 mM) with negligible uptake into the brain (Hawkins et al. 1971). However, upon increasing bHB arterial concentrations by starvation for 2 days or more, cerebral uptake is significantly enhanced (Hawkins et al. 1971). Increased cerebral uptake of bHB has also been shown during development (Hawkins et al. 1971;Dahlquist and Persson 1976), following starvation (Owen et al. 1967) and in diabetes (Kries and Ross 1992). The brain's ability to increase its reliance on bHB appears to be a common form of cerebral metabolic adaptation under conditions of insufficient glucose availability and developmental increases in cerebral energy demand.The evidence for the use of bHB by the brain under conditions of cerebral metabolic stress suggests a role for this alternative substrate in cerebral metabolism after ...

show abstract

Chronic ketosis and cerebral metabolism

DeVivo

Leckie

Ferrendelli

et al. 1978

Annals of Neurology

255

View full text Add to dashboard Cite

The effects of chronic ketosis on cerebral metabolism were determined in adult rats maintained on a high-fat diet for approximately three weeks and compared to a control group of animals. The fat-fed rats had statistically significantly lower blood glucose concentrations and higher blood beta-hydroxybutyrate and acetoacetate concentrations; higher brain concentrations of bound glucose, glucose 6-phosphate, pyruvate, lactate, beta-hydroxybutyrate, citrate, alpha-ketoglutarate, alanine, and adenosine triphosphate (ATP); lower brain concentrations of fructose 1,6-diphosphate, aspartate, adenosine diphosphate (ADP), creatine, cyclic nucleotides, succinyl coenzyme A (CoA), acid-insoluble CoA, and total CoA; and similar brain concentrations of glucose, malate, calculated oxaloacetate, glutamate, glutamine, adenosine monophosphate, phosphocreatine, reduced CoA, acetyl CoA, sodium, potassium, chloride, and water content. The metabolite data in the chronically ketotic rats demonstrate an increase in the cerebral energy reserve and energy charge. These data also suggest negative modification of the enzymes phosphofructokinase, pyruvic dehydrogenase, and alpha-ketoglutaric dehydrogenase; positive modification of glycogen synthase; and possible augmentation of the hexose transport system. There was no demonstrable difference in brain pH, water content, or electrolytes in the two groups of animals. We speculate that the increased brain ATP/ADP ratio is central to most, if not all, the observed metabolic perturbations and may account for the increased neuronal stability that accompanies chronic ketosis.

show abstract

The Rate of Cerebral Utilization of Glucose, Ketone Bodies, and Oxygen: A Comparative in Vivo Study of Infant and Adult Rats

Cited by 74 publications

References 15 publications

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Chronic ketosis and cerebral metabolism

Contact Info

Product

Resources

About