Regional ketone body utilization by rat brain in starvation and diabetes

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...

Section: Implications Of Ketone Body Oxidation For Models Of Neuroenementioning

confidence: 80%

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

Chowdhury

Jiang

Rothman

et al. 2014

“…25 It has been shown that the STZ-treated rats had globally increased CMR glu and cerebral ketone utilization at 1 week. 25,39 The regional CMR glu in almost all the brain regions recovered to normal level at 4 weeks, but this is accompanied by further increased contribution of ketone bodies to brain energy metabolism 25,39 and reduced regional cerebral blood flow in selected brain regions including the striatum. 29 It thus appears that, in response to the evolving consequences of sustained hyperglycemia, the diabetic brain must be in a constant process of adaption trying to reach a new homeostasis state for energy metabolism, and it may make use of alternative substrates such as Glu, in a region-specific manner, 39 under circumstances when these substrates are needed and available.…”

Section: Glutamate Reduction After Insulin Injectionmentioning

confidence: 99%

Region-Specific Cerebral Metabolic Alterations in Streptozotocin-Induced Type 1 Diabetic Rats: An in vivo Proton Magnetic Resonance Spectroscopy Study

Zhang

Huang

Gao

et al. 2015

Clinical and experimental in vivo 1 H-magnetic resonance spectroscopy ( 1 H-MRS) studies have demonstrated that type 1 diabetes mellitus (T1DM) is associated with cerebral metabolic abnormalities. However, less is known whether T1DM induces different metabolic disturbances in different brain regions. In this study, in vivo 1 H-MRS was used to measure metabolic alterations in the visual cortex, striatum, and hippocampus of streptozotocin (STZ)-induced uncontrolled T1DM rats at 4 days and 4 weeks after induction. It was observed that altered neuronal metabolism occurred in STZ-treated rats as early as 4 days after induction. At 4 weeks, T1DM-related metabolic disturbances were clearly region specific. The diabetic visual cortex had more or less normalappearing metabolic profile; while the striatum and hippocampus showed similar abnormalities in neuronal metabolism involving N-acetyl aspartate and glutamate; but only the hippocampus exhibited significant changes in glial markers such as taurine and myo-inositol. It is concluded that cerebral metabolic perturbations in STZ-induced T1DM rats are region specific at 4 weeks after induction, perhaps as a manifestation of varied vulnerability among the brain regions to sustained hyperglycemia.

“…It has been proposed by Cahill (1982) that ketone metabolism may not be important in animals with lower brain/body ratios. Extending this hypothesis further, Hawkins et al (1986) posed an interesting notion that 'whether a requirement for the expansion of the cerebral cortex during the course of human evolution was the improved ability to use ketone bodies during time of need'.…”

Section: Species Differencesmentioning

confidence: 99%

Cerebral Metabolic Adaptation and Ketone Metabolism after Brain Injury

Prins¹

2007

211

184

The developing central nervous system has the capacity to metabolize ketone bodies. It was once accepted that on weaning, the 'post-weaned/adult' brain was limited solely to glucose metabolism. However, increasing evidence from conditions of inadequate glucose availability or increased energy demands has shown that the adult brain is not static in its fuel options. The objective of this review is to summarize the body of literature specifically regarding cerebral ketone metabolism at different ages, under conditions of starvation and after various pathologic conditions. The evidence presented supports the following findings: (1) there is an inverse relationship between age and the brain's capacity for ketone metabolism that continues well after weaning; (2) neuroprotective potentials of ketone administration have been shown for neurodegenerative conditions, epilepsy, hypoxia/ischemia, and traumatic brain injury; and (3) there is an age-related therapeutic potential for ketone as an alternative substrate. The concept of cerebral metabolic adaptation under various physiologic and pathologic conditions is not new, but it has taken the contribution of numerous studies over many years to break the previously accepted dogma of cerebral metabolism. Our emerging understanding of cerebral metabolism is far more complex than could have been imagined. It is clear that in addition to glucose, other substrates must be considered along with fuel interactions, metabolic challenges, and cerebral maturation.