Adipocyte Expression of SLC19A1 Links DNA Hypermethylation to Adipose Tissue Inflammation and Insulin Resistance

• Published in: The journal of clinical endocrinology and metabolism Vol. 103; no. 2; pp. 710 - 721
• Main Authors: Petrus, Paul, Bialesova, Lucia, Checa, Antonio, Kerr, Alastair, Naz, Shama, Bäckdahl, Jesper, Gracia, Ana, Toft, Sofia, Dahlman-Wright, Karin, Hedén, Per, Dahlman, Ingrid, Wheelock, Craig E, Arner, Peter, Mejhert, Niklas, Gao, Hui, Rydén, Mikael
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.02.2018; Oxford University Press
• Subjects: Adipocytes; Adipose tissue; Body fat; Carbon cycle; Chemokines; CpG islands; Deoxyribonucleic acid; DNA; DNA methylation; DNA microarrays; Enzyme-linked immunosorbent assay; Enzymes; Epigenetics; Folic acid; Gene expression; Inflammation; Insulin; Insulin resistance; Metabolomics; Monocyte chemoattractant protein 1; Polymerase chain reaction; siRNA; Transcription
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2017-01382

Abstract Context Insulin resistance (IR) is promoted by a chronic low-grade inflammation in white adipose tissue (WAT). The latter might be regulated through epigenetic mechanisms such as DNA methylation. The one carbon cycle (1CC) is a central metabolic process governing DNA methylation. Objective To identify adipocyte-expressed 1CC genes linked to WAT inflammation, IR, and their causal role. Design Cohort study. Setting Outpatient academic clinic. Participants Obese and nonobese subjects. Methods Gene expression and DNA methylation arrays were performed in subcutaneous WAT and isolated adipocytes. In in vitro differentiated human adipocytes, gene knockdown was achieved by small interfering RNA, and analyses included microarray, quantitative polymerase chain reaction, DNA methylation by enzyme-linked immunosorbent assay and pyrosequencing, protein secretion by enzyme-linked immunosorbent assay, targeted metabolomics, and luciferase reporter and thermal shift assays. Main Outcome Measures Effects on adipocyte inflammation. Results In adipocytes from obese individuals, global DNA hypermethylation was associated positively with gene expression of proinflammatory pathways. Among the 1CC genes, IR in vivo and proinflammatory gene expression in WAT were most strongly and inversely associated with SLC19A1, a gene encoding a membrane folate carrier. SLC19A1 knockdown in human adipocytes perturbed intracellular 1CC metabolism, induced global DNA hypermethylation, and increased expression of proinflammatory genes. Several CpG loci linked SLC19A1 to inflammation; validation studies were focused on the chemokine C-C motif chemokine ligand 2 (CCL2) in which methylation in the promoter (cg12698626) regulated CCL2 expression and CCL2 secretion through altered transcriptional activity. Conclusions Reduced SLC19A1 expression in human adipocytes induces DNA hypermethylation, resulting in increased expression of specific proinflammatory genes, including CCL2. This constitutes an epigenetic mechanism that might link dysfunctional adipocytes to WAT inflammation and IR. We identified a link among insulin resistance, reduced expression of the folate carrier SLC19A1, DNA hypermethylation, and expression of proinflammatory genes in human adipocytes.