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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.
- Source :
-
Journal of Nutritional Biochemistry . Oct2012, Vol. 23 Issue 10, p1207-1213. 7p. - Publication Year :
- 2012
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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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09552863
- Volume :
- 23
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Journal of Nutritional Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 104368693
- Full Text :
- https://doi.org/10.1016/j.jnutbio.2011.07.002