Loss of ACOT7 potentiates seizures and metabolic dysfunction

Am J Physiol Endocrinol Metab. 2019 Nov 1;317(5):E941-E951. doi: 10.1152/ajpendo.00537.2018. Epub 2019 Apr 30.


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 such as an increased startle response. To understand the contribution of Acot7 to seizure susceptibility, we generated Acot7 knockout (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 ACOT7 demonstrating 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.

Keywords: epilepsy; fatty acid; neuron; thioesterase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adiposity
  • Animals
  • Behavior, Animal
  • Diet, High-Fat
  • Excitatory Amino Acid Agonists
  • Female
  • Glucose Intolerance / genetics
  • Kainic Acid
  • Male
  • Metabolic Diseases / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Palmitoyl-CoA Hydrolase / genetics*
  • Pregnancy
  • Seizures / chemically induced
  • Seizures / genetics*
  • Seizures / psychology
  • Weight Gain


  • Excitatory Amino Acid Agonists
  • Acot7 protein, mouse
  • Palmitoyl-CoA Hydrolase
  • Kainic Acid