Acin-Perez, RebecaIborra, SalvadorMartí-Mateos, YolandaCook, Emma CLConde-Garrosa, RuthPetcherski, AntonMuñoz, Mª Del MarMartínez de Mena, RaquelKrishnan, Karthickeyan ChellaJiménez, ConcepciónBolaños, Juan PedroLaakso, MarkkuLusis, Aldon JShirihai, Orian SSancho, DavidEnriquez, Jose Antonio2022-07-072022-07-072020-09Nat Metab. 2020; 2(9):974-988.http://hdl.handle.net/20.500.12105/14683Proinflammatory 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Diet, High-FatMacrophage ActivationAdipose Tissue, WhiteAnimalsBone Marrow CellsFatty LiverInflammationInsulin ResistanceInterleukin-1betaMagnetic Resonance ImagingMice, Inbred C57BLMice, KnockoutMitochondria, LiverObesityProto-Oncogene ProteinsReactive Oxygen Speciessrc-Family KinasesAttribution-NonCommercial-NoDerivatives 4.0 Internacional32943786 29974-98810.1038/s42255-020-00273-82522-5812Nature metabolismopen access