Background: To investigate whether luminal leptin alters ion transport properties of the intestinal epithelium under acute inflammatory conditions. Methods: Monolayers of human intestinal T84 epithelial cells and a rat model of chemotherapy-induced enterocolitis were used. Cells were treated with leptin and mounted in Ussing chambers to measure basal and secretagogue-induced changes in transepithelial short circuit current (Isc). Further, the role of mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating responses to leptin was investigated. Acute colitis in Sprague-Dawley rats was induced by intraperitoneal injection of 40 mg/kg methotrexate (MTX). Results: Leptin (100 ng/ml) induced a time-dependent increase in basal Isc in T84 intestinal epithelial cells (p<0.01). Moreover, pretreatment of T84 cells with leptin for up to 1 hr significantly potentiated carbachol- and forskolin-induced increases in Isc. Pretreatment with an inhibitor of MAPK abolished the effect of leptin on basal, carbachol- and forskolin-induced chloride secretion (p<0.05). However, the PI3K inhibitor, wortmannin, only blunted the effect of leptin on forskolin-induced increases in Isc. Furthermore, leptin treatment evoked both ERK1/2 and Akt1 phosphorylation in T84 cells. In the rat model, luminal leptin induced significant increases in Isc across segments of proximal, and to a lesser extent distal colon (p<0.05). Conclusions: Luminal leptin is likely an intestinal chloride secretagogue, particularly when present at elevated concentrations and/or in the setting of inflammation. Our findings may provide a mechanistic explanation, at least in part, for the clinical condition of secretory diarrhea both in hyperleptinemic obese patients and in patients with chemotherapy-induced intestinal inflammation.
- ion transport
- Copyright © 2009, American Journal of Physiology- Gastrointestinal and Liver Physiology