| First Author | Kim HH | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 6 | Pages | 112636 |
| PubMed ID | 37310859 | Mgi Jnum | J:348694 |
| Mgi Id | MGI:7495407 | Doi | 10.1016/j.celrep.2023.112636 |
| Citation | Kim HH, et al. (2023) xCT-mediated glutamate excretion in white adipocytes stimulates interferon-gamma production by natural killer cells in obesity. Cell Rep 42(6):112636 |
| abstractText | Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-gamma production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-gamma 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-gamma production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-gamma 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-gamma 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. |
