Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/14683
Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity.
Acin-Perez, Rebeca CNIC | Iborra, Salvador CNIC | Martí-Mateos, Yolanda | Cook, Emma C L | Conde-Garrosa, Ruth CNIC | Petcherski, Anton | Muñoz, Mª Del Mar | Martínez de Mena, Raquel | Krishnan, Karthickeyan Chella | Jiménez, Concepción | Bolaños, Juan Pedro | Laakso, Markku | Lusis, Aldon J | Shirihai, Orian S | Sancho, David CNIC | Enríquez, José Antonio
Nat Metab. 2020; 2(9):974-988.
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.
Diet, High-Fat | Macrophage Activation | Adipose Tissue, White | Animals | Bone Marrow Cells | Fatty Liver | Inflammation | Insulin Resistance | Interleukin-1beta | Magnetic Resonance Imaging | Mice, Inbred C57BL | Mice, Knockout | Mitochondria, Liver | Obesity | Proto-Oncogene Proteins | Reactive Oxygen Species | src-Family Kinases
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