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United States Department of Agriculture

Agricultural Research Service

Research Project: ONE-CARBON NUTRIENTS IN THE PREVENTION OF CANCER

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: 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)

Author
item Liu, Zhenhua
item Brooks, Ryan S.
item Ciappio, Eric D.
item Kim, Susan J.
item Crott, Jimmy W.
item Bennett, Grace
item Greenberg, Andrew S.
item 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.

Last Modified: 8/24/2016
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