xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity

Abstract Obesity-mediated hypoxic stress underlies inflammatory responses, 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. We demonstrate that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in hypertrophic adipocytes, leading to NK cell recruitment. Interestingly, the spatial proximity between NK cells and xCT-expressing adipocytes increases IFN-γ production by stimulating metabotropic glutamate receptor 5 (mGluR5) in NK cells, and IFN-γ further augments the expression of xCT and CXCL12 in adipocytes. Consequently, this vicious cycle promotes adipose tissue expansion and inflammation. In contrast, genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells combats obesity and hepatic steatosis and improves glucose tolerance in male mice. Our findings posit that adipose glutamate-induced activation of mGluR5 in NK cells is a novel therapeutic target in obesity-related metabolic disorders.