Previous studies have suggested that docosahexaenoic acid (DHA), contained in fish oil, prevents brain disease. In the current study, the effect of fish oil feeding on gene expression in the brain was investigated by suppression subtractive hybridization. We found that pyruvate dehydrogenase E1 alpha (PDHE1alpha) mRNA expression is down-regulated by fish oil feeding. We examined whether the expression of PDHE1alpha mRNA is altered by DHA treatment in differentiated PC12 cells. PDHE1alpha mRNA was reduced by supplementation of DHA with a significant decrease in cellular ATP level. These results indicate that fish oil feeding might modulate energy metabolism in the brain.