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Cell Reports, VOL 42, ISSUE 6, 112636, JUNE 27, 2023 | https://doi.org/10.1016/j.celrep.2023.112636 xCT-mediated glutamate excretion by white adipocytes stimulates interferon-γ production by natural killer cells in obesity

Hee-Hoon Kim,^1,2,9 Young-Ri Shim,^1,2,9Ha Neul Kim,³ Keungmo Yang,¹ Tom Ryu,¹ Kyurae Kim,¹ Sung Eun Choi,¹ Min Jeong Kim,¹ Chaerin Woo,¹ Katherine Po Sin Chung,¹ Song Hwa Hong,¹ Hyemi Shin,^2,4 Jae Myoung Suh,⁴ Youngae Jung,⁵ Geum-Sook Hwang,⁵ Won Kim,⁶ Seok-Hwan Kim,⁷ Hyuk Soo Eun,³ Je Kyung Seong,^8,* and Won-Il Jeong^1,10,*

¹Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
²Life Science Research Institute, KAIST, Daejeon 34141, Republic of Korea
³Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
⁴Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
⁵Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea
⁶Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea
⁷Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
⁸Korea 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
⁹These authors contributed equally
¹⁰Lead contact

^*Correspondence: 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.

논문정보

형식Research article
게재일2023년 06월 (BRIC 등록일 2023-06-13)
연구진국내 연구진
분야 의약학 > 응용의학

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