Human Cerebral Metabolism in Ketosis

Jullie W. Pan, M.D., Ph.D.

Albert Einstein College of Medicine

Funded in June, 1996: $100000 for 5 years
LAY SUMMARY . BIOGRAPHY . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

INVESTIGATOR BIOGRAPHIES

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Jullie W. Pan, M.D., Ph.D.

Associate Professor
Albert Einstein College of Medicine

HYPOTHESIS

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Hypothesis:
There are significant alterations in cerebral metabolism with ketosis and ketonemia. The researchers believe that defining how ketosis changes metabolism will be important to understanding how the ketogenic diet is efficacious in treating severe epilepsy.

Goals:
To better understand how ketosis alters cerebral metabolism. Specifically, to determine the extent to which ketones contribute towards oxidative metabolism, and the metabolic path by which ketones enter into neurotransmission. With their epilepsy colleagues, the researchers will apply their understanding of the metabolic role of ketones to determine whether such metabolic shifts are important for the control of seizures.

Methods:
To use high field (4T) magnetic resonance spectroscopy in human brain for the cerebral measurements of ketones, lactate, glucose and high energy phosphates. Many of the methods used here have been published in papers that are listed in the bibliography of the papers below. Plasma assays using conventional oxidase measures are used to determine plasma levels of ketones, glucose, and lactate. Mass spectrometry is used to determine 13C content from plasma samples.

Follow-on Funding:
NIH NS40550, 12/01-11/04

FINDINGS

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Scientific Results:
Based on a hypothesis of metabolic and bioenergetic alterations, our original work focused on studying patients on the ketogenic diet using 31P and 1H MR spectroscopy. We reported that the utilization of the ketogenic diet resulted in significant increases in the energetic status as assessed by the ratios of PCr/ATP and PCr/Pi.

The observed energetic changes could be related to the effect of the chronic ketosis in the ketogenic diet and or the energetic improvement that has been reported to accompany improved seizure control. Thus, to better resolve this question, we shifted our attention to understanding how ketones are used and the metabolic changes intrinsic to ketosis. In aims 2 and 3 we evaluated to what extent brain BHB can accumulate in control adults. Under fasting conditions (aim 2), we found that both brain BHB and lactate increased. The increased BHB suggests that ketone oxidation is not limited by its transport across the blood brain barrier, contrary to what has been previously interpreted from rodent and human data. The increase in lactate concentration with fasting may arise as a consequence of reduced metabolic lactate clearance due to a shift from pyruvate to ketone oxidation. A continuous production of lactate through glycolysis has been suggested by Pellerin and Magistretti (1994) to be necessary for clearance of synaptic glutamate under basal and activated levels of neuronal activity.

In aim 3 we established that the brain BHB elevation under non-fasting conditions was much lower, consistent with an upregulation of transport capacity with fasting. This was consistent with earlier animal data, finding inducible transport function under varying physiological conditions. The measurement of brain ketones is necessarily a steady state assessment, reflecting the transport and clearance of ketones. It does not determine to what extent ketones are actually being metabolized.

The last year of Dana support was used to determine the extent to which ketones are consumed. We used 13C NMR spectroscopy with infusion of (non-radioactive) 13C-labeled ketones to perform this study in n=4 adults. We observed that the steady state 13C spectrum from BHB was qualitatively similar to that obtained from a 13C-glucose infusion study. Steady state modeling of the 13C label distribution in glutamate and glutamine in the n=4 subjects suggests that under these conditions, the consumption of the β-hydroxybutyrate is predominantly neuronal, rather than glial. Taken together, these results are consistent with the view that under non-fasted conditions, cerebral ketones minimally accumulate, instead being rapidly used by the neuronal compartment.

The implications of predominantly neuronal consumption is important, given that in the ketosis of the ketogenic diet this may provide a metabolic substrate directed towards the neuronal compartment, without being initially cycled through astrocytes. As stated above from the model of Pellerin and Magistretti, neurons derive a critical fraction of glucose consumption through the transfer of astrocytederived glycolytic lactate, resulting from synaptic glutamate clearance. In this context, BHB may provide a metabolic fuel to the neuron without synaptic glutamate cycling, an edge that may be important in a disorder where neurotransmission is expected to be deranged.

SELECTED PUBLICATIONS

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Pan J.W., Telang F.W., de Graaf R.A., Rothman D.L., Stein D.T., Hetherington H.P.  Human brain β-hydroxybutyrate rises in acute hyperketonemia.  J Neurochem. 2001 Nov;79(3):539-44.

De Graaf R.A., Pan J.W., Telang F.W., Lee J.H., Novotny E.J., Hetherington H.P., and Rothman D.L.  Differentiation of glucose transport in human brain gray and white matter.  J Cereb Blood Flow Metab. 2001 May;21(5):483-92.

Pan J.W., Rothman D.L., Behar K.L., Stein D.T., and Hetherington H.P.  Human brain β-hydroxybutyrate and lactate increase in fasting induced ketosis.  J Cereb Blood Flow Metab. 2000 Oct;20(10):1502-7.

Pan J.W., Bebin E.M., Chu W.J., and Hetherington H.P.  Ketosis and epilepsy: 31P spectroscopic imaging at 4.1T.  Epilepsia. 1999 Jun;40(6):703-7.