We employed IRF9 global KO mice to study the metabolic roles of IRF9 and found a poor hepatic metabolic phenotype. After overexpressing IRF9 specifically in the liver,

nearly all the devastating metabolic effects of IRF9 deficiency were mitigated. This phenomenon reflects the importance of IRF9 in the liver to regulate glucose and lipid metabolism. JQ1 ic50 Probably resulting from the short period of IRF9 overexpression using the adenovirus injection method and the preexistence of endogenous IRF9, the metabolic changes during IRF9 overexpression were, although statistically significant, not as drastic as those during IRF9 deficiency. Despite all these factors, IRF9 was vividly shown to relieve hepatic lipid overabundance and the development of hepatic steatosis in our obesity models. In mammals, the IRF family consists of nine members that share similar structures. Different IRFs have overlapping targets and functions.[12] Some may wonder whether other IRFs compensate for the loss of IRF9 in IRF9 KO mice. Through deletion mutant plasmid construction

and IP mapping, we identified that the less-conserved intermediate region of IRF9, rather than the well-conserved LY294002 DBD or IAD, interacts with PPAR-α. Therefore, the regulation of PPAR-α transactivation could be uniquely attributed to IRF9, rather than other IRF family members. Our study reveals the versatility of IRF9 and broadens our view toward the IRF family, which, as the name implies, was renowned for mediating immune responses. We now have successfully suggested a key role for IRF9 in metabolic function independent of its effect on immunity. However, uncovering the metabolic role of IRF9 in the liver is only the tip of the iceberg. There are many more unanswered questions, such as the tissue specificity of IRF function, interactions among IRFs and multiple cofactors, and influence of one IRF family member on the other family members. Investigating the mechanisms of IRF-mediated metabolic regulation will undoubtedly shed new light on treatment

for obesity and diabetes. The authors thank Dr. Tadatsugu Taniguchi (University 17-DMAG (Alvespimycin) HCl of Tokyo, Tokyo, Japan) for providing the IRF9 knockout mice. The authors also appreciate the RIKEN BRC for shipping IRF9 knockout mice through the National BioResource Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan. Additional Supporting Information may be found in the online version of this article. Supporting table 1. Serum biochemical and cytokine, hormone analysis and liver function analysis kits. Supporting table 2. Primers for Real-time PCR detection. Supporting table 3. Antibodies for immunoblot analyses. Supporting table 4. The primers for making constructs.