Title: IRF3 is a Critical Regulator of Adipose Glucose and Energy Homeostasis
Description: Obesity is associated with a state of chronic inflammation, which is believed to contribute to insulin resistance. We previously identified interferon regulatory factor 3 (IRF3) as an anti-adipogenic transcription factor with high expression in adipocytes. Because IRF3 is known to drive expression of pro-inflammatory genes in immune cells, we hypothesized that it may also promote inflammation and insulin resistance in adipocytes. Consistent with our expectations, we found that the expression of inflammatory genes in adipocytes was induced by IRF3 overexpression, while knockdown of IRF3 had the opposite effect. Despite this effect on local adipocyte gene expression, we found that Irf3-/- mice did not show evidence of altered systemic inflammation. Nonetheless, Irf3-/- mice did display altered metabolism relative to their wild type (WT) littermates.

For example, high fat diet (HFD) fed Irf3-/- mice exhibited increased lean mass and decreased fat mass compared to WT, accompanied by increased food intake and energy expenditure. Further investigation showed that the white adipose tissue (WAT) of Irf3-/- mice had increased expression of brown adipocyte selective genes compared to WT, and the inguinal WAT of the Irf3-/- mouse contain multilocular adipocytes that resemble brown adipocytes. These data suggest that IRF3 affects energy homeostasis by regulating the development of brown adipocyte-like cells in WAT. Additionally, Irf3-/- mice are significantly more insulin sensitive and glucose tolerant compared to WT when kept on HFD. Consistent with in vivo observations, IRF3 knockdown in 3T3-L1 adipocytes resulted in enhanced insulin-stimulated glucose uptake and lipogenesis, while overexpression of constitutively active IRF3 had the opposite effect.

Several IRF3 target genes in adipocytes were identified using transcriptional profiling. Interestingly, the expression level of Slc2a4 (encoding the Glut4 protein) was inversely correlated with that of IRF3 in both WAT and cultured adipocytes. Analysis of the Slc2a4 proximal promoter identified a putative IRF3 binding site upstream of the transcription start site, and luciferase assay in 3T3-L1 adipocytes showed that IRF3 negatively regulates Slc2a4 expression via this site. Taken together, these data indicate that IRF3 plays a role in whole body glucose homeostasis by repressing thermogenic gene expression as well as the expression of adipose Glut4.