INTRODUCTION - Obesity is a major risk factor for gallstone formation. However, the pathogenesis of this phenomenon remains unclear. Gallstones are caused by supersaturation of cholesterol in bile, cholesterol crystal pronucleators, and gallbladder stasis. Human and recent murine studies from this laboratory suggest that in obesity resting gallbladder volume is increased. 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 fat cells, is known to have central effects on neuropeptide Y and cholecystokinin, but the influence of leptin on the biliary effects of these hormones are unknown. Therefore, we tested the hypothesis that leptin-deficient C57BL/6Jlepob obese mice would have decreased gallbladder responses to excitatory stimuli.
METHODS - Twelve-week old C57BL/6Jlepob obese female mice (n=16) and their lean controls (C57BL/6J) (n=18) were fed a non-lithogenic diet. The mice were fasted overnight and underwent cholecystectomy. Whole gallbladders were then placed in 3ml muscle baths. After determining optimal length with acetylcholine (ACh 10-5 M), in-vitro responses to increasing doses of neuropeptide Y (NPY 10-8 M to 10-6 M), and cholecystokinin-octapeptide (CCK-8 10-10 M to 10-7 M) were measured. Student's t-test and two-way ANOVA were used where appropriate. Results were expressed as N/cm2.
RESULTS - Results are shown in the table.
ACh (10-5 M) NPY (10-8 M) NPY (10-7 M) NPY (10-6 M)
Control 0.40 ± 0.08 0.00 ± 0.00 0.12 ± 0.02 0.26 ± 0.08
Obese 0.14 ± 0.04* 0.00 ± 0.00 0.05 ± 0.01* 0.06 ± 0.01*
CCK-8 (10-10 M) CCK-8 (10-9 M) CCK-8 (10-8 M) CCK-8 (10-7 M)
Control 0.27 ± 0.04 0.59 ± 0.08 0.80 ± 0.11 0.86 ± 0.11
Obese 0.13 ± 0.02* 0.27 ± 0.04* 0.37 ± 0.05* 0.44 ± 0.06*
Data are mean ± SEM. * p<0.01 vs. Control.
CONCLUSIONS - These data suggest that genetically obese mice have decreased responses to acetylcholine, neuropeptide Y, and cholecystokinin-octapeptide. We conclude that decreased gallbladder motility contributes to the increased incidence of gallstones associated with obesity.