Obesity is a major risk factor for gallstone formation, but the pathogenesis of this phenomenon remains unclear. Human data on gallbladder emptying are conflicting, and no animal data exist on the effect of obesity on gallbladder motility. Leptin, a hormone produced by adipocytes, is known to have central effects on neuropeptide Y and cholecystokinin, but the influence of leptin on the biliary effects of these hormones is unknown. Therefore we tested the hypothesis that leptin-deficient C57BL/6J-lep(ob) obese mice would have decreased gallbladder responses to excitatory stimuli. Twelve-week-old lean control (C57BL/6J) (n = 22) and C57BL/6J-lep(ob) obese (n = 20) female mice were fed a nonlithogenic diet. The mice were fasted overnight and underwent cholecystectomy. Whole gallbladders were placed in 3 ml muscle baths. After optimal length was determined with acetylcholine (10(-5) mol/L, responses to increasing doses of neuropeptide Y (10(-8) to 10(-6) mol/L) and cholecystokinin-8 (10(-10) to 10(-7) mol/L) were measured. Student's t test and two-way analysis of variance were used where appropriate. Results were expressed as Newtons per cross-sectional area. The lean control mice had significantly greater excitatory responses to acetylcholine than the obese mice (0.37 +/- 0.05 vs. 0.16 +/- 0.02, P < 0.01). The gallbladder responses were also greater when mice were treated with neuropeptide Y (10(-8) mol/L: 0.00 +/- 0.00 vs. 0.00 +/- 0.00, NS; 10(-7) mol/L: 0.12 +/- 0.02 vs. 0.05 +/- 0.01, P < 0.01; 10(-6) mol/L: 0.26 +/- 0.08 vs. 0.06 +/- 0.01, P < 0.01) and cholecystokinin (10(-10) mol/L: 0.27 +/- 0.04 vs. 0.13 +/- 0.02, P < 0.01; 10(-9) mol/L: 0.59 +/- 0.08 vs. 0.27 +/- 0.04, P < 0.01; 10(-8) mol/L: 0.80 +/- 0.11 vs. 0.37 +/- 0.05, P < 0.01; 10(-7) mol/L: 0.86 +/- 0.11 vs. 0.44 +/- 0.06, P < 0.01). These data suggest that genetically obese, leptin-deficient mice have decreased responses to acetylcholine, neuropeptide Y, and cholecystokinin. We conclude that decreased gallbladder motility contributes to the increased incidence of gallstones associated with obesity.