Silent information regulator 2 (Sir2) helps survival and longevity in lower organisms during challenging situations. We investigated the possibility that Sir2α could be involved with brain plasticity under challenging situations. A diet high in saturated fat and sucrose, which has been shown in rodents to reduce synaptic plasticity and cognition, decreased Sir2α levels in the hippocampus and cerebral cortex, in proportion to an increase in protein oxidation. Vitamin E supplementation normalized, in the hippocampus and cerebral cortex, Sir2α levels that had been reduced by the high-fat diet. Neither the high-fat diet nor vitamin E supplementation affected cerebellar Sir2α. Vitamin E reduced, in the hippocampus, the oxidized nucleic acids that were increased by the high-fat diet. Western blot analysis showed higher contents of Sir2α in the hippocampus and cerebellum than in the cerebral cortex. Sir2α immunostaining was predominantly localized in the mossy fibre system and the dentate gyrus granule layer of the hippocampal formation. The high-fat diet decreased Sir2α immunostaining while vitamin E supplementation reversed these effects. Given that oxidative stress is a subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein kinase (AMPK) to have an indication of the energy status of cells. Hippocampal levels of total and phosphorylated AMPK were reduced after high fat consumption and levels were normalized by vitamin E treatment. The present results show that oxidative stress and energy homeostasis associated with the consumption of the high-fat diet are critical for the regulation of Sir2α, with important implications for mechanisms of neural repair.