Regulatory function of interferon regulatory factor 3 in obesity, inflammation and insulin resistance (HUM7P.287)

Obesity is a major risk factor for diseases ranging from insulin resistance, type 2 diabetes mellitus to nonalcoholic fatty liver disease. Obesity is associated with a state of chronic, low-grade inflammation. In this study, we found the important regulatory role of interferon regulatory factor 3 (IRF3), a master regulator of type I interferon-dependent immune responses, in obesity. We found that the expression of IRF3 was increased in white adipose tissue (WAT) from mice fed with high fat diet compared with that from mice fed with normal chow. IRF3 knockout (KO) mice developed obesity spontaneously with increased adiposity compared with wild-type (WT) controls. Deficiency of IRF3 in mice resulted in impaired insulin sensitivity and lipid homeostasis. The development of obesity in IRF3 KO mice was associated with increased infiltration of macrophages which was more inflammatory in the WAT compared with macrophages in WT mice. IRF3 deficient macrophages exhibited increased M1 polarization than WT cells. Additionally, IRF3 KO mice developed hepatic steatosis with increased expression of lipogenesis genes in the liver. Our study therefore demonstrated that IRF3 played an important role in the regulation of insulin sensitivity, inflammation and lipid homeostasis, which may provide a new strategy for treatment of obesity, type 2 diabetes mellitus and hepatic steatosis.