Leptin activation of mTOR pathway in intestinal epithelial cell triggers lipid droplet formation, cytokine production and increased cell proliferation

Abstract

Accumulating evidence suggests that obesity and enhanced inflammatory reactions are predisposing conditions for developing colon cancer. Obesity is associated with high levels of circulating leptin. Leptin is an adipocytokine that is secreted by adipose tissue and modulates immune response and inflammation. Lipid droplets (LD) are organelles involved in lipid metabolism and production of inflammatory mediators, and increased numbers of LD were observed in human colon cancer. Leptin induces the formation of LD in macrophages in a PI3K/mTOR pathway-dependent manner. Moreover, the mTOR is a serine/threonine kinase that plays a key role in cellular growth and is frequently altered in tumors. We therefore investigated the role of leptin in the modulation of mTOR pathway and regulation of lipid metabolism and inflammatory phenotype in intestinal epithelial cells (IEC-6 cells). We show that leptin promotes a dose- and time-dependent enhancement of LD formation. The biogenesis of LD was accompanied by enhanced CXCL1/CINC-1, CCL2/MCP-1 and TGF-β production and increased COX-2 expression in these cells. We demonstrated that leptin-induced increased phosphorylation of STAT3 and AKT and a dose and time-dependent mTORC activation with enhanced phosphorilation of the downstream protein P70S6K protein. Pre-treatment with rapamycin significantly inhibited leptin effects in LD formation, COX-2 and TGF-β production in IEC-6 cells. Moreover, leptin was able to stimulate the proliferation of epithelial cells on a mTOR-dependent manner. We conclude that leptin regulates lipid metabolism, cytokine production and proliferation of intestinal cells through a mechanism largely dependent on activation of the mTOR pathway, thus suggesting that leptin-induced mTOR activation may contribute to the obesity-related enhanced susceptibility to colon carcinoma.

Obesity and cancer: inflammation bridges the two

“…Colonic TNF-α expression is elevated in HFD-fed mice [80], and TNF-α is potent inducer of IL-6 which is known to play a role in promoting colorectal cancer [81]. A recent study found that leptin stimulated the production of IL-6 and TNF-α and promoted proliferation in colon epithelial cells in an mTOR-dependent manner [82]. Adiponectin can inhibit colorectal cancer cell growth through activation of AMPK [83], and loss of adiponectin enhances development of both colitis-associated colorectal cancer and in APC min mice [84].…”

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

“…The monocyte chemoattractant protein (MCP‐1, also known as chemokine ligand 2 [CCL2]) is a central chemokine in mononuclear cell recruitment . In different models such as saturated fatty acid‐ or oxLDL‐rich conditions, leptin stimuli in tumor cells, polymicrobial infection, or LPS‐driven inflammatory responses, the increase in MCP‐1/CCL2 production occurs in parallel to LD formation. Indeed, MCP‐1/CCL2 directly induces a dose‐dependent increase in the numbers of cytoplasmic LDs in vitro within resident peritoneal macrophages isolated from naive mice, indicating that its effect occurs through cell migration independent pathways.…”

The potential role of leptin in tumor invasion and metastasis

“…In a study of normal uterine smooth muscle cells collected from myometrial biopsies, leptin induced cell proliferation at both low and high doses (6.25 and 50 ng/ml) [165]. In the same way, leptin was documented to stimulate the proliferation of normal intestinal epithelial cells (IEC-6 cells) [166]. With regard to the proliferation of cancer cells, the pertinent information has been provided in Table 3 along with a brief etiologic account [116,167–180].…”