In order to identify the potential peripheral signals of appetite and satiety from duodenum, we have performed a transcriptomic study in the mucosa after high-fat (HF) and low-fat (LF) meal ingestion. After fasting, one group of mice was killed and the others were fed ad libitum with HF or LF diet, and killed 30 min, 1 h, and 3 h after the beginning of the meal. The duodenum mucosa was sampled, and the serial analysis of gene expression (SAGE) method was performed. The mRNA regulations were confirmed by real-time PCR. Energy, protein, and fat intakes were higher in the HF than in the LF group. Gene expression profile revealed 118 characterized or partially characterized differentially expressed transcripts. The HF meal delayed the expressions of peptidases compared to the LF groups. Most of mRNAs related to fat absorption, including apolipoprotein A-IV (Apoa4), were decreased in HF1h group, whereas plasma triglyceride (TG) levels were comparable between HF and LF groups. Noteworthy, these downregulations were concomitant to a break in fat intake 1 h after HF meal. At the same time, the HF meal induced transcripts related to cell growth and organization, whereas transcripts involved in cell defense were repressed. Moreover, we have identified fat-responsive transcripts. This study has characterized the molecular responses of duodenum mucosa after HF or LF meal ingestion. Characterization of novel fat-specific candidates whose relations with feeding behavior have never been reported may contribute to the development of new therapeutic targets for appetite and satiety controls.