Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming in the brain during recovery from experimental stroke

Abstract

The goal of this study was to evaluate changes in metabolic homeostasis during the first 12 weeks of recovery in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we compared the brain metabolomes of ipsilateral and contralateral hemispheres from aged male mice up to 12 weeks after stroke to that of age-matched naive and sham operated mice. There were 707 biochemicals detected in each sample by liquid chromatography-mass spectroscopy (LC-MS). Mitochondrial fatty acid {beta}-oxidation, indicated by acyl carnitine levels, was increased in stroked tissue at 1 day and 4 weeks following stroke. Glucose and several glycolytic intermediates were elevated in the ipsilateral hemisphere for 12 weeks compared to the aged naive controls, but pyruvate was decreased. Additionally, itaconate, a glycolysis inhibitor associated with activation of anti-inflammatory mechanisms in myeloid cells, was higher in the same comparisons. These changes correlated with reduced levels of glutamate, dopamine, and adenosine in the ipsilateral hemisphere after stroke. These results indicate that chronic metabolic differences exist between stroked and control tissue, including alterations in fatty acid metabolism and glycolysis for at least 12 weeks after stroke.