Diminished gallbladder motility in Rotund leptin-resistant obese mice

Obesity is a risk factor for cholesterol gallstone formation, but the pathogenesis of this phenomenon remains unclear. Most human obesity is associated with diabetes and leptin-resistance. Previous studies from this laboratory have demonstrated that diabetic leptin-resistant (Lep(db)) obese mice have low biliary cholesterol saturation indices, enlarged gallbladders and diminished gallbladder response to neurotransmitters. Recently, a novel leptin-resistant mouse strain Lepr(db-rtnd) (Rotund) has been discovered. Rotund mice are also obese, diabetic, and have an abnormal leptin receptor. Therefore, we tested the hypothesis that leptin-resistant obese Rotund mice would have large gallbladders and reduced biliary motility.

Eight-week-old control (C57BL/6J, N=12) and Rotund leptin-resistant (Lepr(db-rnd), N=9) mice were fed a non- lithogenic diet for four weeks. Animals were fasted and underwent cholecystectomy. Gallbladder volumes were recorded, and contractile responses (N/cm(2)) to acetylcholine (10(-5) M), Neuropeptide Y (10(-8,-7,-6) M), and cholecystokinin (10(-10,-9,-8,-7) M) were measured. Results were analyzed using the Mann-Whitney Rank Sum Test.

Compared to control mice, Rotund mice had larger body weights, higher serum glucose levels, and greater gallbladder volumes (p<0.05). Rotund gallbladders had less contractility (p<0.05)) to acetylcholine and cholecystokinin than control mice. Responses to Neuropeptide Y were also less, but not statistically significant, in the Rotund mice.

These data suggest that leptin-resistant Rotund mice have (1) enlarged gallbladders with (2) diminished contractility compared to lean control mice. Therefore, this study confirms that leptin-resistance is associated with abnormal biliary motility and may lead to gallstone formation in leptin-resistant obesity.