Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Kubota, Tetsuya; Inoue, Mariko; Kubota, Naoto; Takamoto, Iseki; Mineyama, Tomoka; Iwayama, Kaito; Tokuyama, Kumpei; Moroi, Masao; Ueki, Kohjiro; Yamauchi, Toshimasa; Kadowaki, Takashi
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 15
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07358-9
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophageIrs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specificIrs2 -deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophageIrs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specificIR -deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation ofIrs2 . We conclude that downregulation ofIrs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity. Obesity is associated with low-grade chronic inflammation. Here the authors show that the activation of anti-inflammatory M2a-subtype macrophages requires the IL4/Irs2/Akt pathway. Due to decreased Irs2 expression this pathway is impaired in obese mice thus leading to a defect in M2a activation.