|Brooks, Ryan S.|
|Ciappio, Eric D.|
|Kim, Susan J.|
|Crott, Jimmy W.|
|Greenberg, Andrew S.|
|Mason, Joel B.|
Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/8/2011
Publication Date: 12/29/2011
Citation: Liu, Z., Brooks, R., Ciappio, E., Kim, S., Crott, J., Bennett, G., Greenberg, A., Mason, J. 2011. Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer. Journal of Nutritional Biochemistry. Available: www.sciencedirect.com. Interpretive Summary: Obesity is associated with an increased risk of colorectal cancer, but the underlying mechanism remains unclear. This study investigated whether obesity-promoted inflammation activates a critical colorectal tumorigenic pathway, the Wnt pathway. Mouse studies were conducted and obesity was induced by utilizing a high-fat diet. Colonic inflammatory status was determined and changes of several components in the Wnt pathway were also measured. The data demonstrate that diet-induced obesity produces an elevation in colonic TNF-alpha, a critical inflammatory cytokine, and instigates a number of alterations of key components within the Wnt signaling pathway that are pro-transformational in nature. These observations offer evidence for a biologically plausible avenue, the Wnt pathway, by which obesity increases the risk of colorectal cancer.
Technical 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-alpha). 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-alpha in the colon by 72% (P=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-alpha protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3Beta), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-alpha, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3Beta was elevated in the colonic mucosa of obese mice (P<.02). Moreover, Beta-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-alpha 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.