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Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain.

ABSTRACT: It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-(13)C(3)]heptanoate was examined in the normal mouse brain and in G1D by (13)C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in (13)C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and (13)C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucose-deficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism.

SUBMITTER: Marin-Valencia I

PROVIDER: S-EPMC3564188 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain.

Marin-Valencia Isaac I Good Levi B LB Ma Qian Q Malloy Craig R CR Pascual Juan M JM

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20121017 2

It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic ...[more]

PMID: 23072752

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Project description:Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet.ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.

Project description:ImportanceDisorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients.ObjectiveTo identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin.Design, setting, and participantsUnsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis.InterventionSupplementation of the regular diet with food-grade triheptanoin.Main outcomes and measuresFirst, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements.ResultsOne participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70% (P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin.Conclusions and relevanceTriheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.

Dataset Information

Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain.

Publications

Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain.

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