Abstract
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.
Highlights
Obesity is recognized as a prevalent global health problem
Among the interferon regulatory factor (IRF) family members, Interferon Regulatory Factor 7 (IRF7) and IRF9 mRNAs increased with lipid accumulation, whereas other IRF members only slightly changed during early adipogenesis and lipid accumulation in adipocytes (Fig 2A–2I)
Among 9 isoforms of IRFs, we focused on IRF7, which was based on the mRNA expression pattern of IRFs in adipocytes in vitro and in adipose tissue from high-fat diet (HFD)-fed mice
Summary
Obesity is recognized as a prevalent global health problem. It is associated with increased risks of developing type 2 diabetes [1], cardiovascular diseases [2, 3], certain types of cancer [4] and depression [5]. Precise mechanisms are still unclear, but numerous studies demonstrated that adipocyte dysfunction and subsequent chronic inflammation are the primary defects linking obesity to whole body metabolism and cardiovascular diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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