Gpx4 Deletion-Mediated Macrophage Ferroptosis Alleviates Obesity-Associated Insulin Resistance

Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4^Mac-KO) mice and subjected both Gpx4^Mac-KO and littermate Gpx4^fl/fl mice to a high-fat diet (HFD) for 16 weeks. Metabolic parameters, adipose tissue morphology, hepatic lipid accumulation, and free fatty acid (FFA) metabolism were assessed. The results showed that macrophage-specific deletion of Gpx4 attenuated HFD-induced obesity and improved insulin sensitivity in mice in vivo. Gpx4-deficient mice exhibited lower levels of systemic inflammation, reduced adipocyte hypertrophy, and diminished hepatic steatosis. Deficiency of Gpx4 in macrophages affects FFA metabolism by regulating the expression of FFA breakdown-related genes, such as C/EBP-α, PPARγ, ATGL, Fabp4, and/or LPL, in white adipose tissue and the liver. These beneficial metabolic effects seemed to be associated with enhanced macrophage ferroptosis, suggesting a mechanistic link between Gpx4 deficiency, ferroptosis, and the alleviation of obesity-associated insulin resistance. Our findings identify macrophage GPX4 as a key mediator of obesity-induced insulin resistance and metabolic malfunction. Targeting macrophage GPX4 may represent a promising therapeutic strategy for the treatment of T2D.