However, the underlying mechanisms of obesity-related metabolic d

However, the underlying mechanisms of obesity-related metabolic disorders still remain elusive. Interferon (IFN) regulatory factors (IRFs) are a family of nine transcription

factors (IRF1-IRF9) in mammals.[11] IRFs are involved in cytosolic pattern-recognition receptor- and Toll-like receptor-mediated signal transduction and regulate type I IFN expression.[12] IRFs play central roles in gene-expression regulation in innate immunity and immune cell differentiation.[13] IRFs were also involved in malignant transformation through regulation AZD9668 cost of cell growth and apoptosis.[14] Moreover, we newly observed that cardiovascular diseases, such as cardiac hypertrophic, can be regulated by IRF family members.[15] Besides the above-mentioned factors, metabolic roles of IRFs have also emerged. IRF3 was reported to regulate metabolism-related NRs, such as liver X receptor and retinoid X receptor alpha.[16, 17] Another group found that IRFs regulate adipogenesis and adipocyte lipid metabolism.[18, 19] However, the roles of IRFs in hepatic and whole-body metabolism are unclear. IRF9, an IRF family member, has

previously been characterized as mediating innate immunity by activating IFN-mediated transcription.[20-22] In the present study, we discovered a protective role for IRF9 against metabolic disorders. IRF9 knockout (KO) mice fed a high-fat diet (HFD) had higher levels of obesity-induced inflammation, lower insulin sensitivity, and more severe hepatic steatosis than did wild-type (WT) controls, whereas

liver-specific IRF9 overexpression VX-809 in vivo ameliorated these phenotypes in both diet-induced and genetically (ob/ob) obese mice. Furthermore, we determined that IRF9 up-regulated the expression of PPAR-α target genes. These results suggest that IRF9 improves hepatic lipid metabolism and insulin sensitivity. All protocols were approved by the animal care and use committee of Renmin Hospital of Wuhan University (Wuhan, China). IRF9 KO mice were kindly provided by Dr. Tadatsugu Taniguchi (Department MCE of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan). Ob/ob mice were purchased from The Jackson Laboratory (stock no.: 000632; The Jackson Laboratory, Bar Harbor, ME). Nine-week-old female and 8-week-old male ob/ob mice were used. Eight-week-old male C57BL/6 mice and IRF9 KO mice were fed with either normal chow (NC; protein, 18.3%; fat, 10.2%; carbohydrates, 71.5%; D12450B; Research Diets, Inc., New Brunswick, NJ) or an HFD (protein, 18.1%; fat, 61.6%; carbohydrates, 20.3%; D12492; Research Diets) ad libitum for up to 26 weeks. Detailed protocols for animal experiments were described in the Supporting Materials. To overexpress IRF9 and PPAR-α, we used replication-defective adenoviral vectors encompassing the entire coding region of Flag-tagged IRF9 (obtained from OriGene Technologies, Inc.

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