Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Metab. 2020 Sep;2(9):974-988. doi: 10.1038/s42255-020-00273-8. Epub 2020 Sep 17.
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.
促炎性巨噬细胞是肥胖症发展的关键。此外，激活 Fgr 酪氨酸激酶的活性氧（ROS）也有助于肥胖。在这里，我们表明 Fgr 的缺失会损害促炎性巨噬细胞的极化，同时防止高脂肪饮食（HFD）诱导的肥胖。全身性 Fgr 缺失可增加脂肪分解和肝脏脂肪酸氧化，从而避免脂肪变性。骨髓（BM）来源细胞中 Fgr 的敲除足以防止 HFD 喂养后发生胰岛素抵抗和肝脂肪变性，而 Fgr 表达的 BM 来源细胞的转移可使 Fgr 缺陷型宿主免受 HFD 喂养的保护。线粒体过氧化物的清除足以防止 BM 来源细胞中 Fgr 的激活和 HFD 诱导的肥胖。此外，促炎性巨噬细胞中 Fgr 的表达水平更高，并且与小鼠和人类的肥胖特征相关。因此，我们的发现揭示了线粒体 ROS-Fgr 激酶作为促炎性脂肪组织巨噬细胞激活、饮食诱导肥胖、胰岛素抵抗和肝脂肪变性的关键调节轴。
