Leptin-Resistant Congenitally Obese Mice Have Impaired Gallbladder Motility
Abstracts
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Obesity is a major risk factor for gallstone formation; however, the pathogenesis of this phenomenon remains unclear. The hormone leptin regulates body weight through hypothalamic inhibition of neuropeptide Y (NPY) and cholecystokinin (CCK). Leptin deficiency causes obesity in rodents and in a small percentage of humans. We have previously demonstrated that leptin-deficient congenitally obese mice have increased gallbladder volume and impaired gallbladder response. Furthermore, this phenomenon is ameliorated by daily leptin administration. However, obesity in the majority of humans is associated with leptin resistance rather than leptin deficiency. Therefore, we hypothesized that gallbladder motility would also be impaired in leptin-receptor deficient congenitally obese mice compared to lean control mice. Twelve adult lean control (C57Bl/6J) and twelve adult obese leptin-receptor deficient (Leprdb) mice were fasted overnight, and gallbladders were harvested. Gallbladder volumes (µl) were measured, and contractile response (N/cm2) to acetylcholine (ACh 10-5 M), NPY (10-8,-7,-6 M), and CCK (10-10,-9,-8,-7 M) were determined. Results were analyzed with Mann-Whitney Rank Sum Test. These data suggest that leptin-receptor deficient mice have 1) increased gallbladder volume and 2) impaired gallbladder response to ACh, NPY, and CCK compaired to lean control mice. We conclude that both leptin deficiency and a defective leptin receptor result in gallbladder stasis and an impaired response to neurotransmitters. Thus, leptin-induced alterations in gallbladder motility represent a link between obesity and gallstone formation. |
