N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4+T cell responsiveness

Allison M Meadows; Kim Han; Komudi Singh; Antonio Murgia; Ben D McNally; James A West; Rebecca D Huffstutler; Tiffany M Powell-Wiley; Yvonne Baumer; Julian L Griffin; Michael N Sack

doi:10.1016/j.isci.2023.106578

N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4+T cell responsiveness

Allison M Meadows, Kim Han, Komudi Singh, Antonio Murgia, Ben D McNally, James A West, Rebecca D Huffstutler, Tiffany M Powell-Wiley, Yvonne Baumer, Julian L Griffin, Michael N Sack^* (Corresponding Author)

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

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Abstract

Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers these same immunomodulatory effects on transformed cell lines. To identify serum mediators orchestrating this, metabolomic and lipidomic analysis was performed on serum extracted after a 24-h fast and re-feeding. Bioinformatic integration with concurrent peripheral blood mononuclear cells RNA-seq analysis implicated key metabolite-sensing GPCRs in fasting-mediated immunomodulation. The putative GPR18 ligand N-arachidonylglycine (NAGly) was elevated during fasting and attenuated CD4+T cell responsiveness via GPR18 MTORC1 signaling. In parallel, NAGly reduced inflammatory Th1 and Th17 cytokines levels in CD4+T cells isolated from obese subjects, identifying a fasting-responsive metabolic intermediate that may contribute to the regulation of nutrient-level dependent inflammation associated with metabolic disease.

Original language	English
Article number	106578
Number of pages	19
Journal	iScience
Volume	26
Issue number	5
Early online date	19 Apr 2023
DOIs	https://doi.org/10.1016/j.isci.2023.106578
Publication status	Published - 19 May 2023

Bibliographical note

Acknowledgments
We thank Drs. Zoe Hall and Sonia Liggi of the University of Cambridge Biochemistry Department for their contributions to metabolomics analysis and data processing. Shahin Hassanzadeh of the Laboratory of Mitochondrial Biology and Metabolism for developing the PBMC RNAseq library.Matthew Rodman of the Laboratory of Mitochondrial Biology and Metabolism for preparing lean/obese samples. Dr. Duck-Yeon Lee of the NHLBI Biochemistry Core for NAGly analysis in cell culture. Special thanks to the National Institutes of Health Oxford-Cambridge Scholars Program and the International Biomedical Research Alliance for their sponsorship and support.

Funding: NHLBI Division of Intramural Research (MNS – ZIA-HL005199) and the UK MRC (JLG – MR/P011705/2; UKDRI-5002; MAPUK).

Keywords

Human metabolism
Immunology
Lipidomics
Metabolomics
Transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Meadows_etal_CP_N-aracidonylglycine_Is_VoR
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Cite this

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title = "N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4+T cell responsiveness",

abstract = "Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers these same immunomodulatory effects on transformed cell lines. To identify serum mediators orchestrating this, metabolomic and lipidomic analysis was performed on serum extracted after a 24-h fast and re-feeding. Bioinformatic integration with concurrent peripheral blood mononuclear cells RNA-seq analysis implicated key metabolite-sensing GPCRs in fasting-mediated immunomodulation. The putative GPR18 ligand N-arachidonylglycine (NAGly) was elevated during fasting and attenuated CD4+T cell responsiveness via GPR18 MTORC1 signaling. In parallel, NAGly reduced inflammatory Th1 and Th17 cytokines levels in CD4+T cells isolated from obese subjects, identifying a fasting-responsive metabolic intermediate that may contribute to the regulation of nutrient-level dependent inflammation associated with metabolic disease.",

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author = "Meadows, {Allison M} and Kim Han and Komudi Singh and Antonio Murgia and McNally, {Ben D} and West, {James A} and Huffstutler, {Rebecca D} and Powell-Wiley, {Tiffany M} and Yvonne Baumer and Griffin, {Julian L} and Sack, {Michael N}",

note = "Acknowledgments We thank Drs. Zoe Hall and Sonia Liggi of the University of Cambridge Biochemistry Department for their contributions to metabolomics analysis and data processing. Shahin Hassanzadeh of the Laboratory of Mitochondrial Biology and Metabolism for developing the PBMC RNAseq library.Matthew Rodman of the Laboratory of Mitochondrial Biology and Metabolism for preparing lean/obese samples. Dr. Duck-Yeon Lee of the NHLBI Biochemistry Core for NAGly analysis in cell culture. Special thanks to the National Institutes of Health Oxford-Cambridge Scholars Program and the International Biomedical Research Alliance for their sponsorship and support. Funding: NHLBI Division of Intramural Research (MNS – ZIA-HL005199) and the UK MRC (JLG – MR/P011705/2; UKDRI-5002; MAPUK). ",

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AU - McNally, Ben D

AU - West, James A

AU - Huffstutler, Rebecca D

AU - Powell-Wiley, Tiffany M

AU - Baumer, Yvonne

AU - Griffin, Julian L

AU - Sack, Michael N

N1 - Acknowledgments We thank Drs. Zoe Hall and Sonia Liggi of the University of Cambridge Biochemistry Department for their contributions to metabolomics analysis and data processing. Shahin Hassanzadeh of the Laboratory of Mitochondrial Biology and Metabolism for developing the PBMC RNAseq library.Matthew Rodman of the Laboratory of Mitochondrial Biology and Metabolism for preparing lean/obese samples. Dr. Duck-Yeon Lee of the NHLBI Biochemistry Core for NAGly analysis in cell culture. Special thanks to the National Institutes of Health Oxford-Cambridge Scholars Program and the International Biomedical Research Alliance for their sponsorship and support. Funding: NHLBI Division of Intramural Research (MNS – ZIA-HL005199) and the UK MRC (JLG – MR/P011705/2; UKDRI-5002; MAPUK).

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N2 - Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers these same immunomodulatory effects on transformed cell lines. To identify serum mediators orchestrating this, metabolomic and lipidomic analysis was performed on serum extracted after a 24-h fast and re-feeding. Bioinformatic integration with concurrent peripheral blood mononuclear cells RNA-seq analysis implicated key metabolite-sensing GPCRs in fasting-mediated immunomodulation. The putative GPR18 ligand N-arachidonylglycine (NAGly) was elevated during fasting and attenuated CD4+T cell responsiveness via GPR18 MTORC1 signaling. In parallel, NAGly reduced inflammatory Th1 and Th17 cytokines levels in CD4+T cells isolated from obese subjects, identifying a fasting-responsive metabolic intermediate that may contribute to the regulation of nutrient-level dependent inflammation associated with metabolic disease.

AB - Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers these same immunomodulatory effects on transformed cell lines. To identify serum mediators orchestrating this, metabolomic and lipidomic analysis was performed on serum extracted after a 24-h fast and re-feeding. Bioinformatic integration with concurrent peripheral blood mononuclear cells RNA-seq analysis implicated key metabolite-sensing GPCRs in fasting-mediated immunomodulation. The putative GPR18 ligand N-arachidonylglycine (NAGly) was elevated during fasting and attenuated CD4+T cell responsiveness via GPR18 MTORC1 signaling. In parallel, NAGly reduced inflammatory Th1 and Th17 cytokines levels in CD4+T cells isolated from obese subjects, identifying a fasting-responsive metabolic intermediate that may contribute to the regulation of nutrient-level dependent inflammation associated with metabolic disease.

KW - Human metabolism

KW - Immunology

KW - Lipidomics

KW - Metabolomics

KW - Transcriptomics

U2 - 10.1016/j.isci.2023.106578

DO - 10.1016/j.isci.2023.106578

M3 - Article

C2 - 37128607

SN - 2589-0042

VL - 26

JO - iScience

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IS - 5

M1 - 106578

ER -

N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4+T cell responsiveness

Abstract

Bibliographical note

Keywords

UN SDGs

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