This study investigated the chronic effect of enterostatin on body weight and some of the associated changes in postprandial metabolism. Rats were adapted to 6 hours of food access/day and a choice of low fat (LF) and high fat (HF) food and then given enterostatin or vehicle by an intraperitoneally implanted mini-pump delivering 160 nmol enterostatin/h or vehicle continuously over a 5 day infusion period. Enterostatin resulted in a slight but significant reduction of HF intake and body weight. After the last 6h food access period, enterostatin-treated animals had lower plasma triglyceride and free fatty acid but higher plasma glucose and lactate levels than control animals. Also, enterostatin infusion resulted in increased uncoupling protein 2 (UCP2) expression in various tissues including white adipose tissue (epididymal fat pad) and liver. In contrast, UCP2 was reduced in the pancreas of enterostatin-treated animals, and this was associated with increased plasma levels of insulin and amylin. Whether these two hormones are involved in the observed decreased food intake due to enterostatin remains to be determined. As lipid metabolism appeared to be altered by enterostatin, we also measured peroxisome proliferating activated receptor (PPAR) expression in tissues and observed that PPAR, , 1 and2 expression were modified by enterostatin in epididymal WAT, pancreas and liver. This further links altered lipid metabolism with body weight loss. Our data suggest that alterations in UCP2 and PPAR2 play a role in the control of insulin and amylin release from the pancreas. This implies that enterostatin changes lipid and carbohydrate metabolic pathways in addition to its effects on food intake and energy expenditure.