Glutamine Links Obesity to Inflammation in Human White Adipose Tissue

Cell Metab. 2020 Feb 4;31(2):375-390.e11. doi: 10.1016/j.cmet.2019.11.019. | PubMed

Paul Petrus¹, Simon Lecoutre¹, Lucile Dollet², Clotilde Wiel³, André Sulen⁴, Hui Gao¹, Beatriz Tavira¹, Jurga Laurencikiene¹, Olav Rooyackers⁵, Antonio Checa⁶, Iyadh Douagi¹, Craig E Wheelock⁶, Peter Arner¹, Mark McCarthy⁷, Martin O Bergo³, Laurienne Edgar⁸, Robin P Choudhury⁸, Myriam Aouadi⁴, Anna Krook², Mikael Rydén⁹

1. Department of Medicine (H7), Karolinska Institutet, Stockholm 141 86, Sweden.
2. Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
3. Department of Biosciences and Nutrition (BioNut), H2, Karolinska Institutet, Stockholm 141 86, Sweden.
4. Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Huddinge, Sweden.
5. Perioperative Medicine and Intensive Care, B31, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden.
6. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
7. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK; Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
8. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
9. Department of Medicine (H7), Karolinska Institutet, Stockholm 141 86, Sweden. Electronic address: mikael.ryden@ki.se.

Abstract

While obesity and associated metabolic complications are linked to inflammation of white adipose tissue (WAT), the causal factors remain unclear. We hypothesized that the local metabolic environment could be an important determinant. To this end, we compared metabolites released from WAT of 81 obese and non-obese women. This identified glutamine to be downregulated in obesity and inversely associated with a pernicious WAT phenotype. Glutamine administration in vitro and in vivo attenuated both pro-inflammatory gene and protein levels in adipocytes and WAT and macrophage infiltration in WAT. Metabolomic and bioenergetic analyses in human adipocytes suggested that glutamine attenuated glycolysis and reduced uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) levels. UDP-GlcNAc is the substrate for the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) mediated by the enzyme O-GlcNAc transferase. Functional studies in human adipocytes established a mechanistic link between reduced glutamine, O-GlcNAcylation of nuclear proteins, and a pro-inflammatory transcriptional response. Altogether, glutamine metabolism is linked to WAT inflammation in obesity.

Presented By Paul Petrus