The effects of high-fat (HF) feeding on the gene expression in the small intestine were examined using obesity-resistant A/J mice and obesity-sensitive C57BL/6J (B6) mice. Both strains of mice were maintained on low-fat (LF, 5% fat) or HF (30% fat) diets for two weeks. Oligonucleotide microarray and semi-quantitative RT-PCR analysis revealed that lipid metabolism-related genes including mitochondrial acyl-CoA thioesterase 1, pyruvate dehydrogenase kinase 4, and NADP+-dependent cytosolic malic enzyme were up-regulated by more than 2-fold in both strains of mice. The up-regulated gene expression levels were significantly higher in A/J mice than in B6 mice, suggesting the active lipid metabolism in the small intestine of A/J mice. Experiment Overall Design: Mice were maintained on the LF or HF diet for two weeks. For each group (n=6), pooled total RNA from two mice of average body weight was used for the analysis.