Interferon regulatory factor 7 mediates obesity-associated MCP-1 transcription

• Published in: PloS one Vol. 15; no. 5; p. e0233390
• Main Authors: Kuroda, Masashi, Nishiguchi, Misa, Ugawa, Naho, Ishikawa, Etsuko, Kawabata, Yasuyo, Okamoto, Saya, Sasaki, Waka, Miyatake, Yumiko, Sebe, Mayu, Masumoto, Saeko, Tsutsumi, Rie, Harada, Nagakatsu, Sakaue, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2020; Public Library of Science (PLoS)
• Subjects: Adipocytes; Adipose tissue; Aprotinin; Binding; Biochemistry; Biological response modifiers; Biology and Life Sciences; Body fat; Chromatin; Complications and side effects; CRISPR; Deoxyribonucleic acid; Diabetes; DNA; DNA binding; DNA chips; DNA microarrays; EDTA; Gene expression; Genetic aspects; Genomics; Glucose; Glucose metabolism; Health problems; Hypertrophy; Immunoprecipitation; Inflammation; Information management; Insulin; Insulin resistance; Interferon; Interferon regulatory factor; Interferon regulatory factor 7; Lipid metabolism; Lipids; Luciferase; Medicine and Health Sciences; Messenger RNA; Metabolism; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Mutation; Nutrition; Obesity; Physiological aspects; Plasmids; Principal components analysis; Reporters; Research and Analysis Methods; RNA; Transcription (Genetics); Transcription factors; Type 2 diabetes; University graduates; Japan; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0233390

Hypertrophy, associated with adipocyte dysfunction, causes increased pro-inflammatory adipokine, and abnormal glucose and lipid metabolism, leading to insulin resistance and obesity-related-health problems. By combining DNA microarray and genomic data analyses to predict DNA binding motifs, we identified the transcription factor Interferon Regulatory Factor 7 (IRF7) as a possible regulator of genes related to adipocyte hypertrophy. To investigate the role of IRF7 in adipocytes, we examined gene expression patterns in 3T3-L1 cells infected with a retrovirus carrying the IRF7 gene and found that enforced IRF7 expression induced the expression of monocyte chemoattractant protein-1 (MCP-1), a key initial adipokine in the chronic inflammation of obesity. CRISPR/Cas9 mediated-suppression of IRF7 significantly reduced MCP-1 mRNA. Luciferase assays, chromatin immunoprecipitation PCR analysis and gel shift assay showed that IRF7 transactivates the MCP-1 gene by binding to its proximal Interferon Stimulation Response Element (ISRE), a putative IRF7 binding motif. IRF7 knockout mice exhibited lower expression of MCP-1 in epidydimal white adipose tissue under high-fat feeding conditions, suggesting the transcription factor is physiologically important for inducing MCP-1. Taken together, our results suggest that IRF7 transactivates MCP-1 mRNA in adipocytes, and it may be involved in the adipose tissue inflammation associated with obesity.