TY - JOUR
T1 - Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity
AU - Acín-Pérez, Rebeca
AU - Iborra, Salvador
AU - Martí-Mateos, Yolanda
AU - Cook, Emma C.L.
AU - Conde-Garrosa, Ruth
AU - Petcherski, Anton
AU - Muñoz, Mª ªM
AU - Martínez de Mena, Raquel
AU - Krishnan, Karthickeyan Chella
AU - Jiménez, Concepción
AU - Bolaños, Juan Pedro
AU - Laakso, Markku
AU - Lusis, Aldon J.
AU - Shirihai, Orian S.
AU - Sancho, David
AU - Enríquez, José Antonio
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091192379&partnerID=8YFLogxK
U2 - 10.1038/s42255-020-00273-8
DO - 10.1038/s42255-020-00273-8
M3 - Article
AN - SCOPUS:85091192379
SN - 2522-5812
VL - 2
SP - 974
EP - 988
JO - Nature Metabolism
JF - Nature Metabolism
IS - 9
ER -
