Leptin modulates the expression of secreted and membrane-associated mucins in colonic epithelial cells by targeting PKC, PI3K, and MAPK pathways

Abstract

Mucins play an essential role in the protection and repair of gastrointestinal mucosa. We recently showed that luminal leptin strongly stimulated mucin secretion in vivo in rat colon. In the present study, we challenged the hypothesis that leptin may act directly on goblet cells to induce mucin expression in rat and human intestinal mucin-producing cells (DHE and HT29-MTX). The endoluminal effect of leptin was also studied in vivo in rat perfused colon model. The presence of leptin receptors was demonstrated in the two cell lines by Western blot and RT-PCR. In rat DHE cells, leptin (0.01-10 nmol/l, 60 min) dose dependently increased the secretion of mucins (210 +/- 3% of controls) and the expression of Muc2, Muc3, and Muc4 (twofold basal level) but not of Muc1 and Muc5AC. Luminal perfusion of leptin (60 min, 0.1-100 nmol/l) in rat colon also increased the mRNA level of Muc2, Muc3, and Muc4 but not of Muc1. In human HT29-MTX cells, leptin (0.01-10 nmol/l, 60 min) dose dependently enhanced MUC2, MUC5AC, and MUC4 mRNA levels. These effects were prevented by pretreatment of cells with the leptin mutein L39A/D40A/F41A, which acts as a receptor antagonist. Finally, pathway inhibition experiments suggest that leptin increased mucin expression by activating PKC-, phosphatidyl inositol 3-kinase-, and MAPK-dependent pathways but not the JAK/STAT pathway. In conclusion, leptin may contribute significantly to membrane-associated and secreted mucin production via a direct stimulation of colonic epithelial cells and the activation of leptin receptors. These data are consistent with a role for leptin in regulation of the intestinal barrier function.

Leptin induces migration and invasion of glioma cells through MMP‐13 production

“…Although leptin is able to activate different signaling pathways including PI3K/Akt and MAPK pathways (Cui et al 2006;El Homsi et al 2007;Tang et al 2007), MMP-13 elevation was only antagonized by p38 MAPK inhibitor in C6 glioma cells. Furthermore, inhibition of NF-κB p65 pathways by PDTC, TPCK and Bay 11-7082 also reversed the leptin-induced increase of MMP-13 production.…”

Two Atypical Enteropathogenic Escherichia coli Strains Induce the Production of Secreted and Membrane-Bound Mucins To Benefit Their Own Growth at the Apical Surface of Human Mucin-Secreting Intestinal HT29-MTX Cells

“…To investigate in vitro the production of mucins during aEPEC infection, we used cultured, human, mucin-secreting intestinal HT29-MTX cells (42). The regulation of mucin genes coding for secreted or membrane-bound mucins (13,28,68,79), the production of secreted and membrane-bound mucins (28), MUC5AC mucin exocytosis (28,67), and the upregulation of mucins by an enteric pathogen (6,7,47,49) have previously been reported for these cells. …”

Hormonal Signaling in the Gut

“…This effect is likely mediated by the CNS as intracerebroventricular leptin lowers plasma glucose levels in insulin-deficient rodents (92,93), emphasizing the insulin-independent ability of leptin to lower glucose levels. Interestingly, both STAT3 (83, 84) and PI3K (94) are also present in the gut, and leptin has been shown to activate intestinal STAT3 to protect against infection (95). Therefore, it is possible that leptin acts on STAT3 and/or PI3K in the intestine to affect glucose homeostasis, as it does in the CNS.…”