Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity
| Autor: | Kaito Iwayama, Kohjiro Ueki, Kumpei Tokuyama, Tomoka Mineyama, Mariko Inoue, Iseki Takamoto, Takashi Kadowaki, Masao Moroi, Tetsuya Kubota, Toshimasa Yamauchi, Naoto Kubota |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male General Physics and Astronomy FOXO1 Mice Cell Movement Hyperinsulinemia Macrophage lcsh:Science Mice Knockout Multidisciplinary biology Chemistry Forkhead Box Protein O1 Signal Transduction medicine.medical_specialty Science Diet High-Fat General Biochemistry Genetics and Molecular Biology Article Histone Deacetylases 03 medical and health sciences Insulin resistance Downregulation and upregulation Internal medicine 3T3-L1 Cells Hyperinsulinism medicine Animals Nuclear Receptor Co-Repressor 1 Obesity PI3K/AKT/mTOR pathway Cell Proliferation Macrophages General Chemistry Macrophage Activation medicine.disease IRS2 Coculture Techniques Receptor Insulin Mice Inbred C57BL Insulin receptor 030104 developmental biology Endocrinology Gene Expression Regulation biology.protein Insulin Receptor Substrate Proteins lcsh:Q Interleukin-4 Insulin Resistance STAT6 Transcription Factor Proto-Oncogene Proteins c-akt |
| Zdroj: | Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-15 (2018) |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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