Luminal leptin activates mucin-secreting goblet cells in the large bowel

Abstract

Leptin has been suggested to be involved in tissue injury and/or mucosal defence mechanisms. Here, we studied the effects of leptin on colonic mucus secretion and rat mucin 2 (rMuc2) expression. Wistar rats and ob/ ob mice were used. Secretion of mucus was followed in vivo in the rat perfused colon model. Mucus secretion was quantified by ELISA, and rMuc2 mRNA levels were quantified by real-time RT PCR. The effects of leptin alone or in association with protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) inhibitors on mucin secreted by human mucus-secreting HT29-MTX cells were determined. Leptin was detected in the rat colonic lumen at substantial levels. Luminal perfusion of leptin stimulates mucus-secreting goblet cells in a dose-dependent manner in vivo in the rat. Leptin (10 nmol/l) increased mucus secretion by a factor of 3.5 and doubled rMuc2 mRNA levels in the colonic mucosa. There was no damage to mucosa 24 h after leptin, but the number of stained mucus cells significantly increased. Leptin-deficient ob/ ob mice have abnormally dense mucus-filled goblet cells. In human colonic goblet-like HT29-MTX cells expressing leptin receptors, leptin increased mucin secretion by activating PKC- and PI3K-dependent pathways. This is the first demonstration that leptin, acting from the luminal side, controls the function of mucus-secreting goblet cells. Because the gel layer formed by mucus at the surface of the intestinal epithelium has a barrier function, our data may be relevant physiologically in defence mechanisms of the gastrointestinal tract.

Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficile Colitis

“…One of the possible mechanisms of leptin-mediated bactericidal inflammation could be increased cellular recruitment mediated by the leptin-STAT3 axis; however, other known mechanisms of leptin actions, like increased oxidative species production in neutrophils (36), increased mucin glycoprotein and antimicrobial peptide secretion (41,58,59), and maintenance of epithelial integrity (40), could also contribute to leptin-mediated bactericidal inflammation during acute C. difficile infection and will need further investigation. While our study does not directly quantify the numbers of C. difficile CFU, toxin A/B levels are an accurate measure of the critical C. difficile virulence factors and, in combination with C. difficile-specific GDH levels, are a reliable surrogate to monitor bacterial clearance.…”

Apolipoprotein A-IV: a protein intimately involved in metabolism

“…Consumption of a HFD increases plasma leptin levels in humans and rodents ( 97,102,103 ). Leptin acts on its receptor in enterocytes (104)(105)(106)(107)(108)(109)(110) to attenuate lipidinduced apoA-IV synthesis and secretion ( 103 ). Consumption of a HFD causes an initial increase of plasma apoA-IV levels in rodents, but over time the increase is attenuated ( 57,63,66 ).…”

Leptin, MUC2 and mTOR in Appendiceal Mucinous Neoplasms

“…0.05). Recently, it has been suggested that leptin contributes to the production of mucins such as MUC2 and MUC5AC in colonic epithelial cells [11,12] . Thus, leptin may be involved in mucin-producing carcinogenesis as well as in mucin production.…”

“…According to a recent study, leptin contributes to mucin production in colonic epithelial cells, and a leptininduced increment of mucins, such as MUC2, MUC5AC and MUC4, has been reported [11,12] . We had previously reported that MUC2 and MUC5AC were related to the malignant behaviour of appendiceal mucinous neoplasms [6] .…”