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,
Min Jeong 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
Affiliations
Hee-Hoon Kim
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Life Science Research Institute, KAIST, Daejeon 34141, Republic of Korea
Young-Ri Shim
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Life Science Research Institute, KAIST, Daejeon 34141, Republic of Korea
Ha Neul Kim
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
Keungmo Yang
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Tom Ryu
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Kyurae Kim
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Sung Eun Choi
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Min Jeong Kim
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Chaerin Woo
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Katherine Po Sin Chung
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Song Hwa Hong
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Hyemi Shin
Life Science Research Institute, KAIST, Daejeon 34141, Republic of Korea; Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Jae Myoung Suh
Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
Youngae Jung
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea
Geum-Sook Hwang
Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea
Won Kim
Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea
Seok-Hwan Kim
Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
Hyuk Soo Eun
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
Je Kyung Seong
Korea Mouse Phenotyping Center (KMPC) and BK21 Program for Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Corresponding author
Won-Il Jeong
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Corresponding author
Summary: 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.
