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

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 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.

SUBMITTER: Kubota T

PROVIDER: S-EPMC6242852 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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

Kubota Tetsuya T Inoue Mariko M Kubota Naoto N Takamoto Iseki I Mineyama Tomoka T Iwayama Kaito K Tokuyama Kumpei K Moroi Masao M Ueki Kohjiro K Yamauchi Toshimasa T Kadowaki Takashi T

Nature communications 20181119 1

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, resul ...[more]

PMID: 30451856

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Project description:ObjectiveSystemic low-grade inflammation associated with obesity and metabolic syndrome is a strong risk factor for the development of diabetes mellitus and associated cardiovascular complications. This inflammatory state is caused by release of proinflammatory cytokines by macrophages, especially in adipose tissue. Long noncoding RNAs regulate macrophage activation and inflammatory gene networks, but their role in macrophage dysfunction during diet-induced obesity has been largely unexplored. Approach and Results: We sequenced total RNA from peritoneal macrophages isolated from mice fed either high-fat diet or standard diet and performed de novo transcriptome assembly to identify novel differentially expressed mRNAs and long noncoding RNAs. A top candidate long noncoding RNA, macrophage inflammation-suppressing transcript (Mist), was downregulated in both peritoneal macrophages and adipose tissue macrophages from high-fat diet-fed mice. GapmeR-mediated Mist knockdown in vitro and in vivo upregulated expression of genes associated with immune response and inflammation and increased modified LDL (low-density lipoprotein) uptake in macrophages. Conversely, Mist overexpression decreased basal and LPS (lipopolysaccharide)-induced expression of inflammatory response genes and decreased modified LDL uptake. RNA-pull down coupled with mass spectrometry showed that Mist interacts with PARP1 (poly [ADP]-ribose polymerase-1). Disruption of this RNA-protein interaction increased PARP1 recruitment and chromatin PARylation at promoters of inflammatory genes, resulting in increased gene expression. Furthermore, human orthologous MIST was also downregulated by proinflammatory stimuli, and its expression in human adipose tissue macrophages inversely correlated with obesity and insulin resistance.ConclusionsMist is a novel protective long noncoding RNA, and its loss during obesity contributes to metabolic dysfunction and proinflammatory phenotype of macrophages via epigenetic mechanisms.

Dataset Information

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

Publications

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

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