Leptin regulates gallbladder genes related to absorption and secretion

Abstract

Dysregulation of gallbladder ion and water absorption and/or secretion has been linked to cholesterol crystal and gallstone formation. We have recently demonstrated that obese, leptin-deficient (Lep(ob)) mice have enlarged gallbladder volumes and decreased gallbladder contractility and that leptin administration to these mice normalizes gallbladder function. However, the effect of leptin on gallbladder absorption/secretion is not known. Therefore, we sought to determine whether leptin would alter the expression of genes involved in water and ion transport across the gallbladder epithelium. Affymetrix oligonucleotide microarrays representing 39,000 transcripts were used to compare gallbladder gene-expression profiles from 12-wk-old control saline-treated Lep(ob) and from leptin-treated Lep(ob) female mice. Leptin administration to Lep(ob) mice decreased gallbladder volume, bile sodium concentration, and pH. Leptin repletion upregulated the expression of aquaporin 1 water channel by 1.3-fold and downregulated aquaporin 4 by 2.3-fold. A number of genes involved in sodium transport were also influenced by leptin replacement. Epithelial sodium channel-alpha and sodium hydrogen exchangers 1 and 3 were moderately downregulated by 2.0-, 1.6-, and 1.3-fold, respectively. Carbonic anhydrase-IV, which plays a role in the acidification of bile, was upregulated 3.7-fold. In addition, a number of inflammatory cytokines that are known to influence gallbladder epithelial cell absorption and secretion were upregulated. Thus leptin, an adipocyte-derived cytokine involved with satiety and energy balance, influences gallbladder bile volume, sodium, and pH as well as multiple inflammatory cytokine genes and genes related to water, sodium, chloride, and bicarbonate transport.

Diet-induced obesity in zebrafish shares common pathophysiological pathways with mammalian obesity

“…LEP, an adiposity hormone produced by white AT, reflects total fat mass [64]. Although we did not detect a statistically significant difference between OF8W and OF1W in terms of the mRNA expression level of lep measured by qPCR (data not shown), the expression of apoa1 , a transcriptional target gene of leptin [65], was significantly induced and reduced by OF and CR, respectively (Figures 4A and 5B) [Additional files 1, 2 and 7: Supplemental Tables S1 and S2, and Figure S1], suggesting that leptin protein levels were likely to be increased in zebrafish DIO. It is noteworthy that the functional importance of SREBP1, PPARα/γ, NR3H1 and LEP in obesity has been shown in many genetic studies [2,11,63,66].…”

Increased Leptin and Leptin Receptor Expression in Dogs With Gallbladder Mucocele

“…These findings suggest that overexpression of leptin and leptin receptors in GBM patients may reflect a compensatory reaction to resolve biliary dyskinesia caused by decreased motility of the gallbladder and sphincter of Oddi. Another study showed that leptin decreased gallbladder volume, bile sodium concentration, and pH by regulating gallbladder genes related to absorption and secretion . Specifically, leptin upregulated the expression of aquaporin 1 downregulated aquaporin 4 and influenced sodium channel‐α and sodium–hydrogen exchangers .…”

Steatocholecystitis and Fatty Gallbladder Disease

“…Gallbladder contractility and its response to neurotransmitters correlate inversely with serum glucose, insulin, cholesterol, and triglycerides [51]. Administration of leptin to leptin-deficient mice restores gallbladder contractility and decreases gallbladder dry weight [58,59]. The leptin-deficient obesity in these mice causes nonalcoholic fatty gallbladder disease with diminished gallbladder contractility [21].…”