title: Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice.
abstract: Obesity is a calorie-excessive state associated with high risk of diabetes, atherosclerosis, and certain types of tumors. Obesity may induce inflammation and insulin resistance (IR). We found that the expression of interferon (IFN) regulatory factor 9 (IRF9), a major transcription factor mediating IFN responses, was lower in livers of obese mice than in those of their lean counterparts. Furthermore, whole-body IRF9 knockout (KO) mice were more obese and had aggravated IR, hepatic steatosis, and inflammation after chronic high-fat diet feeding. In contrast, adenoviral-mediated hepatic IRF9 overexpression in both diet-induced and genetically (ob/ob) obese mice showed markedly improved hepatic insulin sensitivity and attenuated hepatic steatosis and inflammation. We further employed a yeast two-hybrid screening system to investigate the interactions between IRF9 and its cofactors. Importantly, we identified that IRF9 interacts with peroxisome proliferator-activated receptor alpha (PPAR-α), an important metabolism-associated nuclear receptor, to activate PPAR-α target genes. In addition, liver-specific PPAR-α overexpression rescued insulin sensitivity and ameliorated hepatic steatosis and inflammation in IRF9 KO mice.
  
  
  CONCLUSIONS
  IRF9 attenuates hepatic IR, steatosis, and inflammation through interaction with PPAR-α.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Xin-An
authors.initials: XA
authors.lastname: Wang
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.forename: Dingsheng
authors.initials: D
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Deng
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zhong
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Shufen
authors.initials: S
authors.lastname: Hong
authors.forename: Sen
authors.initials: S
authors.lastname: Guo
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: She
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000503:physiopathology*; D005260:Female; D007333:Insulin Resistance / Q000502:physiology*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D047495:PPAR gamma / Q000502:physiology; D012737:Sex Factors
chemical_list: D004041:Dietary Fats; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D047495:PPAR gamma; C494228:Isgf3g protein, mouse