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
Affiliations
Allison M. Meadows
Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA; Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
Kim Han
Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA
Komudi Singh
Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA
Antonio Murgia
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
Ben D. McNally
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
James A. West
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
Rebecca D. Huffstutler
Cardiovascular Branch, NHLBI, NIH, Bethesda, MD, USA
Tiffany M. Powell-Wiley
Social Determinants of Obesity and Cardiovascular Risk Laboratory, NHLBI, NIH, Bethesda, MD, USA
Yvonne Baumer
Social Determinants of Obesity and Cardiovascular Risk Laboratory, NHLBI, NIH, Bethesda, MD, USA
Julian L. Griffin
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; The Rowett Institute, School of Medicine, Medical Sciences and Nutrition, Foresterhill Campus, Aberdeen, UK
Michael N. Sack
Laboratory of Mitochondrial Biology and Metabolism, NHLBI, NIH, Bethesda, MD, USA; Cardiovascular Branch, NHLBI, NIH, Bethesda, MD, USA; Corresponding author
Summary: 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.
