xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity
Hee‐Hoon Kim, Young‐Ri Shim, Ha‐Neul Kim, Keungmo Yang, Tom Ryu, Kyurae Kim, Sung Eun Choi, Minjeong Kim, Chaerin Woo, Katherine Po Sin Chung, Song Hwa Hong, Hyemi Shin, Jae Myoung Suh, Youngae Jung, Geum‐Sook Hwang, Won Kim, Seok‐Hwan Kim, Hyuk Soo Eun, Je Kyung Seong, Won‐Il Jeong
Abstract
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.