The Innate Immune Factor IRF3 Reduces Adipose Thermogenesis via ISG15-mediated Reprogramming of Cellular Metabolism

Purpose: Interferon regulatory factor 3 (IRF3) is activated by pro-inflammatory cytokines, but its role in regulating adaptive thermogenesis and energy expenditure remains unclear. Here, we report that IRF3 as a negative transcription regulator of adaptive thermogenesis. Adipocyte-specific IRF3 knockout (FI3KO) attenuates HFD-induced obesity by increasing energy expenditure; further studies show that IRF3 suppresses adaptive thermogenesis through ISG15-mediated inhibition of glycolysis in adipocytes. Conversely, overexpression of IRF3 in adipocytes causes reduced thermogenesis gene expression, energy expenditure, and more persistent to HFD-induced obesity. Moreover, Isg15-/- increases adipose thermogenesis and protects mice from HFD-induced obesity and glucose intolerance. Taken together, these data indicate that IRF3 as a transcriptional regulator connecting between inflammatory signaling pathway and energy homeostasis Methods: primary adipocyte mRNA profiles of 8-week-old wild-type (WT) and FI3OE mice were generated by deep sequencing. The sequence reads that passed quality filters were analyzed at the transcript isoform level. qRT–PCR validation was performed using RT-PCR. Conclusions: Our study represents the first detailed analysis of adipocyte transcriptomes from WT and FI3OE iWAT, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that Irf3 adipocyte-speficic overrxpression markedly increases the expression of Isg15 and Herc6, which play important role in regulation of glycolysis. primary adipocyte mRNA profiles of 8-week-old old wild type (WT) and FI3OE mice