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

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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Irs2</jats:italic> expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific <jats:italic>Irs2</jats:italic>-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 <jats:italic>Irs2</jats:italic> expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific <jats:italic>IR</jats:italic>-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 <jats:italic>Irs2</jats:italic>. We conclude that downregulation of <jats:italic>Irs2</jats:italic> in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity.</jats:p>

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