Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

Abstract

Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity-induced elevation of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Animal studies were conducted on C57BL/6 mice, and obesity was induced by utilizing a high-fat diet (60% kcal). An inflammation-specific microarray was performed, and results were confirmed with real-time polymerase chain reaction. The array revealed that diet-induced obesity increased the expression of TNF-α in the colon by 72% (P=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-α protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3β), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-α, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3β was elevated in the colonic mucosa of obese mice (P<.02). Moreover, β-catenin, the key effector of canonical Wnt signaling, was elevated in the colons of obese mice (P<.05), as was the expression of a downstream target gene, c-myc (P<.05). These data demonstrate that diet-induced obesity produces an elevation in colonic TNF-α and instigates a number of alterations of key components within the Wnt signaling pathway that are protransformational in nature. Thus, these observations offer evidence for a biologically plausible avenue, the Wnt pathway, by which obesity increases the risk of colorectal cancer.

Immunologic impact of the intestine in metabolic disease

“…In the colon, the data are less consistent. Some studies have shown increased TNF-α, but not IL-6, at the mRNA level after short-and long-duration HFD feeding (74,75), while other studies have reported no differences (73,76). After ten or 30 days of HFD feeding, intestinal APCs (MHC2 + CD19 -) show reduced activation markers such as CD86 and a reduced ability to induce Th17 cells in vitro, but also show an upregulation of certain inflammatory gene such as Nlrp3 (49).…”

Obesity and thyroid cancer

“…Liu et al (2012) demonstrated that diet-induced obesity produces an elevation in colonic TNFa levels and instigates a number of alterations in the key components within the Wnt signaling pathway, which have a pro-transformational nature, indicating that the Wnt pathway could be the mechanism by which obesity increases the risk of colorectal cancer. TNFa has an anti-proliferative action in a human PTC cell line through a receptor-mediated mechanism (Pang et al 1994).…”

Inflammation Driven Activation of Wnt Pathway: A Potential Mechanism Responsible for Obesity-associated Colorectal Cancer

“…53 IL-1β, another critical inflammatory cytokines shown to be increased in obese state, also exhibits the function to phosphorylate GSK3β, stabilize β-catenin protein, enhance T-cell factor dependent gene activation and induced the expression of Wnt target genes in colonic tumor cells. 54 Nava P et al reported that IFN-γ can regulate intestinal epithelial homeostasis through converging β-catenin signaling pathway.…”

“…In addition to the increased TNF-α in the colon of obese mice reported by our group. 53 An inflammatory state in association with obesity also exists in other organs such as liver, pancreas, muscle and even brain. 56 The inflammatory cytokines produced locally may even have a more direct influence in modulating the local microenvironment, including the regulation of the Wnt pathway.…”