title: Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization.
abstract: Interferon regulatory factors (IRFs) play functionally diverse roles in the transcriptional regulation of the immune system. We have previously shown that several IRFs are regulators of adipogenesis and that IRF4 is a critical transcriptional regulator of adipocyte lipid handling. However, the functional role of IRF4 in adipose tissue macrophages (ATMs) remains unclear, despite high expression there. Here we show that IRF4 expression is regulated in primary macrophages and in ATMs of high-fat diet-induced obese mice. Irf4(-/-) macrophages produce higher levels of proinflammatory cytokines, including interleukin-1β and tumor necrosis factor-α, in response to fatty acids. In coculture experiments, IRF4 deletion in macrophages leads to reduced insulin signaling and glucose uptake in 3T3-L1 adipocytes. To determine the macrophage-specific function of IRF4 in the context of obesity, we generated myeloid cell-specific IRF4 knockout mice, which develop significant insulin resistance on a high-fat diet, despite no difference in adiposity. This phenotype is associated with increased expression of inflammatory genes and decreased insulin signaling in adipose tissue, skeletal muscle, and liver. Furthermore, Irf4(-/-) ATMs express markers suggestive of enhanced M1 polarization. These findings indicate that IRF4 is a negative regulator of inflammation in diet-induced obesity, in part through regulation of macrophage polarization.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Jun
authors.initials: J
authors.lastname: Eguchi
authors.forename: Xingxing
authors.initials: X
authors.lastname: Kong
authors.forename: Masafumi
authors.initials: M
authors.lastname: Tenta
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.forename: Sona
authors.initials: S
authors.lastname: Kang
authors.forename: Evan D
authors.initials: ED
authors.lastname: Rosen
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016764:Cell Polarity; D002478:Cells, Cultured; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D005947:Glucose; D050835:Interferon Regulatory Factors; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000099218:Interferon Regulatory Factor-4