ABSTRACT 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.
Wu et al. (Mon,) studied this question.
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