Proinflammatory macrophages are key in the development of obesity. In addition, reactive oxygen species (ROS), which activate the Fgr tyrosine kinase, also contribute to obesity. Here we show that ablation of Fgr impairs proinflammatory macrophage polarization while preventing high-fat diet (HFD)-induced obesity in mice. Systemic ablation of Fgr increases lipolysis and liver fatty acid oxidation, thereby avoiding steatosis. Knockout of Fgr in bone marrow (BM)-derived cells is sufficient to protect against insulin resistance and liver steatosis following HFD feeding, while the transfer of Fgr-expressing BM-derived cells reverts protection from HFD feeding in Fgr-deficient hosts. Scavenging of mitochondrial peroxides is sufficient to prevent Fgr activation in BM-derived cells and HFD-induced obesity. Moreover, Fgr expression is higher in proinflammatory macrophages and correlates with obesity traits in both mice and humans. Thus, our findings reveal the mitochondrial ROS–Fgr kinase as a key regulatory axis in proinflammatory adipose tissue macrophage activation, diet-induced obesity, insulin resistance and liver steatosis.

促炎巨噬细胞是肥胖发展的关键。此外，激活 Fgr 酪氨酸激酶的活性氧 (ROS) 也会导致肥胖。在这里，我们表明 Fgr 的消融会损害促炎性巨噬细胞极化，同时防止高脂肪饮食 (HFD) 诱导的小鼠肥胖。Fgr 的全身消融会增加脂肪分解和肝脏脂肪酸氧化，从而避免脂肪变性。敲除骨髓 (BM) 衍生细胞中的 Fgr 足以在 HFD 喂养后防止胰岛素抵抗和肝脂肪变性，而表达 Fgr 的 BM 衍生细胞的转移恢复了 Fgr 缺陷宿主对 HFD 喂养的保护。线粒体过氧化物的清除足以防止 BM 衍生细胞中的 Fgr 激活和 HFD 诱导的肥胖。而且，Fgr 在促炎巨噬细胞中的表达较高，并且与小鼠和人类的肥胖特征相关。因此，我们的研究结果揭示了线粒体 ROS-Fgr 激酶是促炎脂肪组织巨噬细胞激活、饮食诱导的肥胖、胰岛素抵抗和肝脂肪变性的关键调节轴。