OBJECTIVE: Postprandial glucagon-like peptide 1 (GLP-1) release seems to be attenuated in obese subjects. Results on whether weight loss improves GLP-1 release are contradictory. The aim of this study was to further investigate the effect of weight loss on basal and postprandial GLP-1 release in overweight/obese subjects. RESEARCH METHODS AND PROCEDURES: Thirty-two overweight/obese subjects participated in a repeated measurement design before (BMI, 30.3 +/- 2.8 kg/m2; waist circumference, 92.6 +/- 7.8 cm; hip circumference, 111.1 +/- 7.4 cm) and after a weight loss period of 6 weeks (BMI, 28.2 +/- 2.7 kg/m2; waist circumference, 85.5 +/- 8.5 cm; hip circumference, 102.1 +/- 9.2 cm). During weight loss, subjects received a very-low-calorie diet (Optifast) to replace three meals per day. Subjects came to the laboratory fasted, and after a baseline blood sample, received a standard breakfast (1.9 MJ). Postprandially, blood samples were taken every one-half hour relative to intake for 120 minutes to determine GLP-1, insulin, glucose, and free fatty acids from plasma. Appetite ratings were obtained with visual analog scales. RESULTS: After weight loss, postprandial GLP-1 concentrations at 30 and 60 minutes were significantly lower than before weight loss (p < 0.05). Glucose concentrations were also lower, and free fatty acids were higher compared with before weight loss. Ratings of satiety were increased, and hunger scores were decreased after weight loss (p < 0.05). DISCUSSION: In overweight/obese subjects, GLP-1 concentrations after weight loss were decreased compared with before weight loss, and nutrient-related stimulation was abolished. This might be a response to a proceeding negative energy balance. Satiety and GLP-1 seem to be unrelated in the long term.