Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression

Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers. [Display omitted] ► Obesity promotes hepatocellular carcinoma (HCC) in mice via TNF and IL-6 cytokines ► TNF and IL-6 promote liver fat accumulation and fat-induced liver inflammation ► Loss of TNF receptor 1 prevents fat-induced liver injury and HCC development ► Ablation of the IL-6 gene also prevents obesity-promoted HCC development