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  • Title: Tumor necrosis factor-α knockout mitigates intestinal inflammation and tumorigenesis in obese Apc1638N mice.
    Author: Li J, Tang Y, Lin TC, Zeng H, Mason JB, Liu Z.
    Journal: J Nutr Biochem; 2023 Jul; 117():109355. PubMed ID: 37085057.
    Abstract:
    Strong evidence from observational studies shows that having body fatness is associated with an individual's risk of developing colorectal cancer (CRC), but the causality between obesity and CRC remains inadequately elucidated. Our previous studies have shown diet-induced obesity is associated with elevated TNF-α and enhanced activation of Wnt-signaling, yet the causal role of TNF-α on intestinal tumorigenesis has not been precisely studied. The present study aims to examine the functionality of TNF-α in the development of CRC associated with obesity. We first examined the extent to which diet-induced obesity elevates intestinal tumorigenesis by comparing Apc1638N mice fed a low fat diet (LFD, 10 kcal% fat) with those fed a high fat diet (HFD, 60 kcal% fat), and then investigated the degree that the genetic ablation of TNF-α attenuates the effect by crossing the TNF-α-/- mice with Apc1638N mice and feeding them with the same HFD (TNF-α KO HFD). After 16-weeks of feeding, the HFD significantly increased intestinal tumorigenesis, whereas the deletion of TNF-α attenuated the effect (P < .05). Accompanying the changes in macroscopic tumorigenesis, HFD significantly elevated intestinal inflammation and procarcinogenic Wnt-signaling, whereas abolishment of TNF-α mitigated the magnitude of these elevations (P < .05). In summary, our findings demonstrate that the knockout of TNF-α attenuates obesity-associated intestinal tumorigenesis by decreasing intestinal inflammation and thereby the Wnt-signaling, indicating that TNF-α signaling is a potential target that can be utilized to reduce the risk of CRC associated with obesity.
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