The purpose of this study was to investigate whether
luminal leptin alters ion transport properties of the intestinal epithelium under acute inflammatory conditions. Monolayers of human intestinal T(84) 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 (I(sc)). Furthermore, the role of 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.
Leptin (100 ng/ml) induced a time-dependent increase in basal I(sc) in T(84) intestinal epithelial cells (P < 0.01). Moreover, pretreatment of T(84) cells with
leptin for up to 1 h significantly potentiated
carbachol- and
forskolin-induced increases in I(sc). 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 I(sc). Furthermore,
leptin treatment evoked both ERK1/2 and Akt1 phosphorylation in T(84) cells. In the rat model,
luminal leptin induced significant increases in I(sc) across segments of proximal and, to a lesser extent, distal colon (P < 0.05). We conclude that
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.