Background & Aims: The presence of nutrients in the small intestine slows gastric emptying and suppresses appetite and food intake; these effects are partly mediated by the release of gut hormones, including cholecystokinin. We investigated the hypothesis that the modulation of antropyloroduodenal motility, suppression of appetite, and stimulation of cholecystokinin and glucagon-like peptide-1 secretion by intraduodenal fat are dependent on triglyceride hydrolysis by lipase. Methods: 16 healthy, young, lean men were studied twice in double-blind, randomised, cross-over fashion. Ratings for appetite-related sensations, antropyloroduodenal motility and plasma cholecystokinin and glucagon-like peptide-1 concentrations were measured during a 120 min duodenal infusion of a triglyceride emulsion (2.8 kcal/min), on one day with, on the other without, 120 mg tetrahydrolipstatin, a potent lipase inhibitor. Immediately following the duodenal fat infusion, food intake at a buffet lunch was quantified. Results: Lipase inhibition with tetrahydrolipstatin was associated with reductions in tonic and phasic pyloric pressures, increased numbers of isolated antral and duodenal pressure waves and stimulation of antropyloroduodenal pressure wave sequences (all P<0.05). Scores for prospective consumption and food intake at lunch were greater, and nausea scores slightly less, and the rises in plasma cholecystokinin and glucagon-like peptide-1 were abolished (all P<0.05). Conclusion: Lipase inhibition attenuates the effects of duodenal fat on antropyloroduodenal motility, appetite and cholecystokinin and glucagon-like peptide-1 secretion.