PMID- 37310859
OWN - NLM
STAT- MEDLINE
DCOM- 20231013
LR  - 20231013
IS  - 2211-1247 (Electronic)
VI  - 42
IP  - 6
DP  - 2023 Jun 27
TI  - xCT-mediated glutamate excretion in white adipocytes stimulates interferon-gamma 
      production by natural killer cells in obesity.
PG  - 112636
LID - S2211-1247(23)00647-2 [pii]
LID - 10.1016/j.celrep.2023.112636 [doi]
AB  - 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.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Kim, Hee-Hoon
AU  - Kim HH
AD  - 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.
FAU - Shim, Young-Ri
AU  - Shim YR
AD  - 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.
FAU - Kim, Ha Neul
AU  - Kim HN
AD  - Department of Internal Medicine, College of Medicine, Chungnam National 
      University, Daejeon 35015, Republic of Korea.
FAU - Yang, Keungmo
AU  - Yang K
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Ryu, Tom
AU  - Ryu T
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Kim, Kyurae
AU  - Kim K
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Choi, Sung Eun
AU  - Choi SE
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Kim, Min Jeong
AU  - Kim MJ
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Woo, Chaerin
AU  - Woo C
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Chung, Katherine Po Sin
AU  - Chung KPS
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Hong, Song Hwa
AU  - Hong SH
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea.
FAU - Shin, Hyemi
AU  - Shin H
AD  - Life Science Research Institute, KAIST, Daejeon 34141, Republic of Korea; 
      Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, 
      Republic of Korea.
FAU - Suh, Jae Myoung
AU  - Suh JM
AD  - Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, 
      Republic of Korea.
FAU - Jung, Youngae
AU  - Jung Y
AD  - Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science 
      Institute, Seoul 03759, Republic of Korea.
FAU - Hwang, Geum-Sook
AU  - Hwang GS
AD  - Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science 
      Institute, Seoul 03759, Republic of Korea.
FAU - Kim, Won
AU  - Kim W
AD  - Department of Internal Medicine, Seoul National University College of Medicine, 
      Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of 
      Korea.
FAU - Kim, Seok-Hwan
AU  - Kim SH
AD  - Department of Surgery, College of Medicine, Chungnam National University, Daejeon 
      35015, Republic of Korea.
FAU - Eun, Hyuk Soo
AU  - Eun HS
AD  - Department of Internal Medicine, College of Medicine, Chungnam National 
      University, Daejeon 35015, Republic of Korea.
FAU - Seong, Je Kyung
AU  - Seong JK
AD  - 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. Electronic address: 
      snumouse@snu.ac.kr.
FAU - Jeong, Won-Il
AU  - Jeong WI
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon 34141, Republic of Korea. Electronic address: wijeong@kaist.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230612
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 0 (SLC7A11 protein, human)
RN  - 0 (Slc7a11 protein, mouse)
RN  - 0 (Amino Acid Transport System y+)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Adipocytes, White/metabolism
MH  - *Glutamic Acid/metabolism
MH  - *Interferon-gamma/metabolism
MH  - Killer Cells, Natural/metabolism
MH  - *Obesity/metabolism
MH  - Amino Acid Transport System y+/metabolism
OTO - NOTNLM
OT  - CP: Immunology
OT  - CP: Metabolism
OT  - glutamate
OT  - interferon-gamma
OT  - metabolic disorders
OT  - metabotropic glutamate receptor
OT  - natural killer cells
OT  - obesity
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2023/06/13 19:15
MHDA- 2023/10/04 06:43
CRDT- 2023/06/13 12:35
PHST- 2022/12/02 00:00 [received]
PHST- 2023/05/22 00:00 [revised]
PHST- 2023/05/26 00:00 [accepted]
PHST- 2023/10/04 06:43 [medline]
PHST- 2023/06/13 19:15 [pubmed]
PHST- 2023/06/13 12:35 [entrez]
AID - S2211-1247(23)00647-2 [pii]
AID - 10.1016/j.celrep.2023.112636 [doi]
PST - ppublish
SO  - Cell Rep. 2023 Jun 27;42(6):112636. doi: 10.1016/j.celrep.2023.112636. Epub 2023 
      Jun 12.