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Am J Physiol Endocrinol Metab. 2019 Apr 30. doi: 10.1152/ajpendo.00537.2018. [Epub ahead of print]

Loss of ACOT7 potentiates seizures and metabolic dysfunction.

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Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
Department of Physiology, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 25878, United States.


Neurons uniquely antagonize fatty acid utilization by hydrolyzing the activated form of fatty acids, long chain acyl-CoAs, via the enzyme acyl-CoA thioesterase 7, Acot7. The loss of Acot7 results in increased fatty acid utilization in neurons and exaggerated stimulus-evoked behavior. To understand the contribution of Acot7 to seizure susceptibility we generated Acot7 KO mice and assayed their response to kainate-induced seizures. Acot7 KO mice exhibited potentiated behavioral and molecular indices of seizure severity following kainic acid administration suggesting that fatty acid metabolism in neurons can be a critical regulator of neuronal activity. These data are consistent with the presentation of seizures in a human with genomic deletion of ACOT7demonstrating the conservation of function across species. To further understand the metabolic complications arising from a deletion in Acot7, we subjected Acot7 KO mice to a high-fat diet. While the loss of Acot7 did not result in metabolic complications following a normal chow diet, a high-fat diet induced greater body weight gain, adiposity and glucose intolerance in Acot7 KO mice. These data demonstrate that Acot7, a fatty acid metabolic enzyme highly enriched in neurons, regulates both brain-specific metabolic processes related to seizure susceptibility and the whole-body response to dietary lipid.


Epilepsy; Fatty Acid; Neuron; Thioesterase


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