Leptin-resistant obese mice do not form biliary crystals on a high cholesterol diet

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<h2>Abstract</h2> <b>Introduction:</b> Human obesity is associated with leptin resistance, elevated serum lipids, hepatic steatosis, and cholesterol gallstone formation. We have previously demonstrated that leptin-resistant (Lep^db) obese mice fed a low cholesterol diet have enlarged gallbladders, but a decreased cholesterol saturation index, despite marked hepatic steatosis and elevated serum cholesterol. However, obese humans typically consume a high cholesterol diet and are prone to form gallstones. Therefore, we tested the hypothesis that on a high cholesterol diet, leptin-resistant obese mice would have large gallbladders, cholesterol saturated bile, and would readily form biliary crystals. <b>Methods:</b> Eight week old female lean control (C57BL/6J, n=70) and leptin-resistant (Lep^db, n=72) mice were fed a 1% cholesterol diet for four weeks. At 12 weeks, all animals were fasted overnight and underwent cholecystectomies. Gallbladder volume (μl) was measured and grouped into 7 lean control and 12 Lep^db pools for determination of cholesterol saturation index (CSI). Bile was examined for cholesterol crystals under polarized light microscopy (#/hpf). Serum cholesterol (mg/dl) and leptin levels (ng/ml) also were measured. Results were analyzed using the Student's t-test. TABLE—ABSTRACT P57GB volCSICrystalsSerum XOLLeptinLean19.1 ± 0.91.15 ± .102.2 ± 0.5131 ± 76 ± 0Lep^db35.8 ± 2.2∗0.91 ± .10†0.0 ± 0.0∗278 ± 10∗229 ± 8∗∗P < 0.001.†P < 0.03 vs C57b lean controls.<b>Conclusions:</b> These data suggest that leptin-resistant obese mice fed a high cholesterol diet have 1) increased gallbladder volume, 2) decreased biliary cholesterol saturation and crystal formation despite 3) elevated serum cholesterol compared to lean control mice. Therefore, we conclude that the link among obesity, diet, and gallstone formation does not require hypersecretion of biliary cholesterol and may be related to gallbladder stasis.