Determining the Bioenergetic Capacity for Fatty Acid Oxidation in the Mammalian Nervous System

ABSTRACT

The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid β-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2^B−/−). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids in vitro and in vivo. Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.

KEYWORDS:

• bioenergetics
• brain
• fatty acid
• lipid
• mitochondria
• neurochemistry

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SUPPLEMENTAL MATERIAL

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ACKNOWLEDGMENTS

This work was supported in part by National Institutes of Health (NIH) grants R01NS072241 to M.J.W., R01NS110808 and R01NS111230 to S.S., and F31NS102151 to C.J.W. C.J.W. was additionally supported by NIH grant T32GM007445, awarded to the Biochemistry, Cellular and Molecular Biology Graduate Program at Johns Hopkins School of Medicine.

We thank the Johns Hopkins Applied Imaging Mass Spectrometry (AIMS) Core Facility at the Johns Hopkins University School of Medicine for undertaking the MALDI imaging in this project.

We have no competing financial interests.

C.J.W., J.L., J.C., S.S., T.C., and M.J.W. performed experiments and wrote the manuscript.