Abstract
BackgroundCytokines secreted by adipose tissue macrophages (ATMs) significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. However, little relevant information is available regarding the role of microvesicles (MVs) derived from ATMs in macrophage-adipocyte crosstalk.MethodsMVs were generated by stimulation of M1 or M2 phenotype THP-1 macrophages and incubated with human primary mature adipocytes and differentiated adipocytes. Subsequently, insulin-stimulated phosphorylation of Akt (pAkt) and glucose uptake were determined. Glucose transporter 4 (GLUT4) translocation and nuclear translocation of nuclear factor (NF)-kappa B were also analyzed in treated adipocytes.ResultsM1 macrophage-derived MVs (M1 MVs) significantly reduced protein abundance of insulin-induced Akt phosphorylation in human primary mature adipocytes and differentiated adipocytes, when compared with the same concentration of M2 macrophage-derived MVs (M2 MVs). In contrast to M2 MVs, which enhanced the insulin-induced glucose uptake measured by 2-NBDG, M1 MVs decreased this effect in treated adipocytes. M1 MVs treatment also brought about a significant increase in the nuclear translocation of nuclear factor (NF)-kappa B, coupled with a decrease in pAkt level and GLUT4 translocation compared with M2 MVs-treated adipocytes. These effects were reversed by BAY 11–7085, a NF- kappa B specific inhibitor.ConclusionsMVs derived from proinflammatory (M1) macrophages may, at least in part, contribute to the pathogenesis of obesity-induced insulin resistance, reducing insulin signal transduction and decreasing glucose uptake in human adipocytes, through NF-kappa B activation. Therefore, these MVs may be potential therapy candidates for the management of type 2 diabetes mellitus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-015-0016-3) contains supplementary material, which is available to authorized users.
Highlights
Cytokines secreted by adipose tissue macrophages (ATMs) significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity
The possibility remains that monocyte/macrophage-secreted MVs can inhibit insulin signaling in adipocytes, thereby causing the insulin resistance observed in obese adipose tissue
We clearly demonstrated that MVs derived from inflamed macrophages (M1 MVs) decreased the insulin-stimulated phosphorylation of Akt protein through enhancement of Nuclear factor kappa B (NF-κB) activation and they blocked glucose uptake by blunting signaling responses that lead to glucose transporter (GLUT4) translocation to the cell surface
Summary
Cytokines secreted by adipose tissue macrophages (ATMs) significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. The general understanding is that ATMs are mainly subdivided into M1 (classically activated or pro-inflammatory) and M2 (alternatively activated or Microvesicles (MVs), known as extracellular vesicles, microparticles, exosomes, or shedding vesicles, are small (30–1000 nm) membrane-bound particles released from eukaryotic cells under normal physiological and pathological conditions. They play a pivotal role in mediating cell-to-cell communication [10]. MVs released by adipocytes play a major role in the crosstalk between adipocytes and macrophages; this crosstalk is recognized as a major mechanism in adipose tissue inflammation and a key contributor to insulin resistance [20, 21]. The possibility remains that monocyte/macrophage-secreted MVs can inhibit insulin signaling in adipocytes, thereby causing the insulin resistance observed in obese adipose tissue
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