Iron Overload Protects from Obesity by Ferroptosis

Dysregulation in iron metabolism is associated with obesity, type 2 diabetes, and other metabolic diseases, whereas the underlying mechanisms of imbalanced glycolipid metabolism are still obscure. Here, we demonstrated that iron overload protected mice from obesity both with normal diets (ND) or high-fat diets (HFD). In iron-overload mice, the body fat was significantly decreased, especially when fed with HFD, excessive iron mice gained 15% less weight than those without iron supplements. Moreover, glucose tolerance and insulin sensitivity were all significantly reduced, and hepatic steatosis was prevented. Furthermore, these mice show a considerable decrease in lipogenesis and lipidoses of the liver. Compared with control groups, iron treated groups showed a 79% decrease in the protein level of Perilipin-2 (PLIN2), a protein marker for lipid droplets. These results were consistent with their substantial decrease in adiposity. RNA-seq and signaling pathway analyses showed that iron overload caused ferroptosis in the liver of mice with a decrease in GPX4 expression and an increase in Ptgs2 expression, resulting in a high level of lipid peroxidation. Overall, this study reveals the protective function of iron overload in obesity by triggering the imbalance of glucolipid metabolism in the liver and highlights the crucial role of ferroptosis in regulating lipid accumulation.