Purpose

The alpha7 nicotinic acetylcholine receptor (α7nAChR), involved in the modulation of inflammation and insulin sensitivity, is downregulated in white adipose tissue (WAT) of obese patients. This study aims to test the ability of a selective synthetic α7nAChR agonist, the spirocyclic Δ²-isoxazoline derivative (R)-(−)-ICH3 (ICH3), to counteract acute inflammation and obesity-associated modifications in WAT.

Methods

We employed the LPS-septic shock murine model, human primary adipocytes and diet-induced obese (DIO) mice. Inflammatory factor expression was assessed by ELISA and quantitative real-time PCR. Flow cytometry was employed to define WAT inflammatory infiltrate. Insulin signaling was monitored by quantification of AKT phosphorylation.

Results

In the septic shock model, ICH3 revealed antipyretic action and reduced the surge of circulating cytokines. In vitro, ICH3 stimulation (10 µM) preserved viability of human adipocytes, decreased IL-6 mRNA (P < 0.05) and blunted LPS-induced peak of TNFα (P < 0.05) and IL-6 (P < 0.01). Chronic administration of ICH3 to DIO mice was associated with lower numbers of CD8+ T cells (P < 0.05) and to changed WAT expression of inflammatory factors (Hp, P < 0.05; CD301/MGL1, P < 0.01; Arg-1, P < 0.05). As compared to untreated, ICH3 DIO mice exhibited improved insulin signaling in the skeletal muscle (P < 0.01) mirrored by an improved response to glucose load (ipGTT: P < 0.05 at 120 min).

Conclusions

We proved that ICH3 is an anti-inflammatory drug, able to reduce inflammatory cytokines in human adipocytes and to blunt the effects of obesity on WAT inflammatory profile, on glucose tolerance and on tissue insulin sensitivity.

中文翻译：

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ICH3是一种选择性的α7烟碱乙酰胆碱受体激动剂，可调节与肥胖相关的脂肪细胞炎症。

目的

肥胖患者的白色脂肪组织（WAT）中的α7烟碱乙酰胆碱受体（α7nAChR）参与炎症和胰岛素敏感性的调节。本研究旨在检验选择性合成α7nAChR激动剂的能力，该螺环Δ ² -isoxazoline衍生物（[R ）- （ - ） - ICH3（ICH3），以抵消急性炎症和WAT肥胖相关的修改。

方法

我们采用了LPS败血性休克小鼠模型，人类原代脂肪细胞和饮食诱发的肥胖（DIO）小鼠。通过ELISA和定量实时PCR评估炎性因子表达。流式细胞仪用于定义WAT炎性浸润。通过定量AKT磷酸化来监测胰岛素信号。

结果

在败血性休克模型中，ICH3具有解热作用并减少了循环细胞因子的激增。在体外，ICH3刺激（10 µM）保留了人脂肪细胞的活力，降低了IL-6 mRNA（P  <0.05），并使LPS诱导的TNFα 和IL-6峰值显着减弱（P <0.05）（P  <0.01）。ICH3长期给予DIO小鼠与CD8 + T细胞数量减少（P  <0.05）和炎症因子的WAT表达改变有关（Hp，P  <0.05; CD301 / MGL1，P  <0.01; Arg-1，P  < 0.05）。与未经治疗的相比，ICH3 DIO小鼠的骨骼肌胰岛素信号改善（P <0.01）反映出对葡萄糖负荷的改善反应（ipGTT： 120分钟时P <0.05）。

结论

我们证明了ICH3是一种抗炎药，能够减少人脂肪细胞中的炎性细胞因子，并抑制肥胖对WAT炎性谱，葡萄糖耐量和组织胰岛素敏感性的影响。