Adipocyte Fas Signaling Promotes MetaInflammation in Obesity Through Its Interaction With Bmx

Background: Obesity-related chronic low-grade inflammation contributes to metabolic disorders. We aimed to explore mechanisms by which the Fas signaling in adipocytes promotes inflammation. Results: We found that the expression of Fas was elevated in adipose tissues from high-fat diet (HFD)-fed obese mice via tumor necrosis factor-α (TNF-α). Inflammation response was attenuated in adipose tissues from global FasL deficient (gld) mice. In contrast, activation of Fas signaling by Fas-activating antibody promoted release of TNF-α and IL-6, without significant impact on adipocyte growth. Mechanistically, activation of NF-κB and MAPK pathways and release of TNF-α and IL-6 by Fas signaling was mediated by interaction of Fas with Bmx, a non-receptor tyrosine kinase. Phosphorylation of Fas at Tyr189 residue is required for its interaction with Bmx on SH2 domain. Further, knockdown of Bmx abolished the effects of Fas activation on proinflammatory response in adipocytes. Fas/Bmx complex involved in the adipose tissue inflammation via Fas at Tyr189 site and SH2 domain of Bmx. Conclusion: This study uncovers the proinflammatory effect of Fas/Bmx signaling pathway in adipocytes in obesity, and provides new clues for the development of new treatments for obesity-associated metabolic diseases.