Consumption of the fish oil high-fat diet uncouples obesity and mammary tumor growth through induction of reactive oxygen species in pro-tumor macrophages

Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in pro-tumor macrophages. Compared to FA components in both HFD, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the pro-tumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA-mediated ROS production and macrophage death in vitro and in vivo . Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated pro-tumor macrophage death in an A-FABP dependent manner.