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

iScience. 2023 Apr 6;26(5):106578. doi: 10.1016/j.isci.2023.106578. eCollection 2023 May 19.

Authors

Allison M Meadows^{1

2}, Kim Han¹, Komudi Singh¹, Antonio Murgia², Ben D McNally², James A West², Rebecca D Huffstutler³, Tiffany M Powell-Wiley⁴, Yvonne Baumer⁴, Julian L Griffin^{2

5}, Michael N Sack^{1

3}

Affiliations

¹ Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA.
² Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK.
³ Cardiovascular Branch, NHLBI, NIH, Bethesda, MD, USA.
⁴ Social Determinants of Obesity and Cardiovascular Risk Laboratory, NHLBI, NIH, Bethesda, MD, USA.
⁵ The Rowett Institute, School of Medicine, Medical Sciences and Nutrition, Foresterhill Campus, Aberdeen, UK.

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.

Keywords: Human metabolism; Immunology; Lipidomics; Metabolomics; Transcriptomics.