Leptin regulates gallbladder genes related to gallstone pathogenesis in leptin-deficient mice

BACKGROUND: Little is known about the genetic factors that cause alterations in gallbladder motility, cholesterol crystal nucleation, biliary lipids, and, ultimately, cholesterol gallstones. Obese, leptin-deficient (Lep(ob)) mice have large gallbladder volumes with decreased contraction in vitro and are predisposed to cholesterol crystal formation. Leptin administration to these mice causes weight loss and restores gallbladder function. We hypothesize that administration of leptin to Lep(ob) mice would cause weight loss, decrease gallbladder volume, and change gallbladder genes related to gallbladder motility, nucleating factors, and lipid metabolism. STUDY DESIGN: Twenty-four 8-week-old Lep(ob) mice were fed a nonlithogenic diet for 4 weeks. Twelve mice received daily IP saline injections, and 12 received 5 mu g/g recombinant leptin. Gallbladder mRNA was pooled and analyzed on murine genome microarray chips. Selected genes were confirmed by real-time polymerase chain reaction (PCR) in a second group of mice treated by the same protocol. RESULTS: Leptin-deficient mice given leptin had significant weight loss and reductions in gallbladder volume. These mice had upregulation of the leptin receptor (p=0.007; PCR=1.1-fold increase) but downregulation of leptin (p=0.003; PCR 13.5-fold decrease). Leptin upregulated the cholecystokinin A receptor (p < 0.001; PCR=3.1-fold increase), acetylcholine beta 2 receptor (p=0.005), and the Ca+-calmodulin - dependent protein kinase (p=0.002) genes. Leptin also altered immunoglobulin heavy chain 4 (p=0.005; PCR = 17.7-fold increase), mucin 3 (p=0.006), and carboxylesterase (p=0.016; PCR = 2.5-fold decrease) genes. Leptin downregulated 3-hydroxy 3-methylglutaryl coenzyme A reductase (p=0.006; PCR = 2.5-fold decrease) and LDL receptor (p=0.003). CONCLUSIONS: Leptin modulates obesity and regulates gallbladder genes related to cholesterol gallstone pathogenesis.