Congenitally obese mice are hyperphagic, suggesting that their obesity is secondary to defects in normal satiety mechanisms. The present study compares the effects of caerulein, bombesin, and pancreatic polypeptide (three equimolar doses each of 3, 9, and 27 nmol/kg) on food intake in 10 pairs of lean and obese mice. After the intraperitoneal injection of saline, obese mice eat 240% more of a liquid meal (Magnacal) than their lean littermates (P less than 0.01). All three doses of caerulein significantly inhibited food intake in both obese and lean mice. Although the highest dose of bombesin significantly decreased food intake in both obese and lean mice, the lowest dose was only effective in obese mice. In contrast, none of these doses of pancreatic polypeptide had a significant effect on food intake in either lean or obese mice. A dose of bovine pancreatic polypeptide of 200 nmol/kg was required to significantly reduce food intake in lean and obese mice. This study demonstrates that obese mice respond to satiety signals and may even be more sensitive than their lean littermates to some messengers. In addition, the previously described reversal of this obesity syndrome by pancreatic polypeptide in doses of approximately 2.5 and 25 nmol X kg-1 X day-1 is unlikely to be due to effects of this peptide on food intake.