Apical leptin induces chloride secretion by intestinal epithelial cells and in a rat model of acute chemotherapy-induced colitis

作者：Hoda M Raschid; Scharl Michael; Keely Stephen J; McCole Declan F; Barrett Kim E^*

来源：American Journal of Physiology - Gastrointestinal and Liver Physiology, 2010, 298(5): G714-G721.

DOI：10.1152/ajpgi.00320.2009

• intestinal ion transport

Hoda MR, Scharl M, Keely SJ, McCole DF, Barrett KE. Apical leptin induces chloride secretion by intestinal epithelial cells and in a rat model of acute chemotherapy-induced colitis. Am J Physiol Gastrointest Liver Physiol 298: G714-G721, 2010. First published March 4, 2010; doi:10.1152/ajpgi.00320.2009.-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.

• 出版日期2010-5