Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity

• Published in: Nature communications Vol. 9; no. 1; pp. 4863 - 15
• Main Authors: Kubota, Tetsuya, Inoue, Mariko, Kubota, Naoto, Takamoto, Iseki, Mineyama, Tomoka, Iwayama, Kaito, Tokuyama, Kumpei, Moroi, Masao, Ueki, Kohjiro, Yamauchi, Toshimasa, Kadowaki, Takashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-11-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/21; 13/31; 13/51; 38; 38/15; 692/699; 692/699/249; 692/699/317; AKT protein; Cell activation; FOXO1 protein; Humanities and Social Sciences; Hyperinsulinemia; Impairment; Insulin; Insulin resistance; Interleukin 4; Macrophages; Mice; multidisciplinary; Obesity; Science; Science (multidisciplinary); Stat6 protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07358-9

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 macrophage
Irs2
expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific
Irs2
-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 macrophage
Irs2
expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific
IR
-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 of
Irs2
. We conclude that downregulation of
Irs2
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.