Leucine injections directly into the brain decrease food intake whereas supplementation of this amino acid in a diet has a negligible effect on food intake. We sought to investigate why orally supplemented leucine is ineffective as an anorexigen. We found that mice consuming leucine exhibited increased cFos immunoreactivity in the ARC and PVN of hypothalamus, areas controlling energy balance. However, real time- PCR analysis of the hypothalamic tissue in mice that were exposed to oral leucine showed changes in expression of genes involved in the regulation of energy balance as well as those mediating feeding reward (TMEM18, MC4R, CRH, FTO, SLC6A15, DOR). This suggests that leucine consumption affects activity of not only brain pathways that control calorie intake, but also those that mediate eating for pleasure. Hence the lack of feeding response to leucine supplementation in a diet may stem from the simultaneous action of this amino acid at brain circuit promoting reward and energy homeostasis.