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Kim, Hee-Hoon; Shim, Young-Ri; Kim, Ha Neul; Yang, Keungmo; Ryu, Tom; Kim, Kyurae; Choi, Sung Eun; Kim, Min Jeong; Woo, Chaerin; Chung, Katherine Po Sin; Hong, Song Hwa; Shin, Hyemi; Suh, Jae Myoung; Jung, Youngae; Hwang, Geum-Sook; Kim, Won; Kim, Seok-Hwan; Eun, Hyuk Soo; Seong, Je Kyung; Jeong, Won-Il
Cell reports (Cambridge), 06/2023, Letnik: 42, Številka: 6Journal Article
Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4+ NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders. Display omitted •Hypoxic adipocytes recruit NK cells through CXCL12 and excrete glutamate by xCT•mGluR5 activation in CXCR4+ NK cells exerts IFN-γ production and inflammation•NK cell-derived IFN-γ augments the glutamate and CXCL12 production by adipocytes•Bidirectional crosstalk between adipocytes and NK cells mediates obesity and NAFLD Kim et al. show that hypoxia induces xCT-mediated glutamate excretion and CXCL12 expression in adipocytes, recruiting CXCR4+ NK cells. This spatial proximity provokes IFN-γ production by NK cells via mGluR5 activation, reinforcing glutamate and CXCL12 production by adipocytes. Consequently, this bidirectional interaction between adipocytes and NK cells instigates obesity.
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in: SICRIS
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