Type I interferon sensing unlocks dormant adipocyte inflammatory potential

White adipose tissue inflammation, in part via myeloid cell contribution, is central to obesity pathogenesis. Mechanisms regulating adipocyte inflammatory potential and consequent impact of such inflammation in disease pathogenesis remain poorly defined. We show that activation of the type I interferon (IFN)/IFNα receptor (IFNAR) axis amplifies adipocyte inflammatory vigor and uncovers dormant gene expression patterns resembling inflammatory myeloid cells. IFNβ-sensing promotes adipocyte glycolysis, while glycolysis inhibition impeded IFNβ-driven intra-adipocyte inflammation. Obesity-driven induction of the type I IFN axis and activation of adipocyte IFNAR signaling contributes to obesity-associated pathogenesis in mice. Notably, IFNβ effects are conserved in human adipocytes and detection of the type I IFN/IFNAR axis-associated signatures positively correlates with obesity-driven metabolic derangements in humans. Collectively, our findings reveal a capacity for the type I IFN/IFNAR axis to regulate unifying inflammatory features in both myeloid cells and adipocytes and hint at an underappreciated contribution of adipocyte inflammation in disease pathogenesis.

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Data Senad Divanovic
As stated in the methods section, for RNA-sequencing analysis, all transcriptomic analyses were performed in StrandNGS aligned with the genome using UCSC. For pathway analysis, the database at toppgene.cchmc.org was employed.
As noted in the methods section, all statistical data analysis was performed via GraphPad Prism 8 Software. Flow cytometry was analyzed FlowJo software. GEO generated from RNA-seq analysis through TopGene. Transcription factor binding site motif enrichment was analyzed using the HOMER motif enrichment algorithm.

March 2018
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All experimental findings were reproduced, with the exception of RNA-sequencing analyses and reciprocal bone marrow transfer experiment, a minimum of 2-3 times and all replication attempts were successful. Representative genes from RNA-sequencing analyses were validated and can be found in Supplementary Figure 2c.
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No blinding was used in this study given that the HFD-driven obesity models utilized in these studies leads to mice with easily distinguishable sizes.
As described in the methods section, antibodies used were the following: