Low-dose decitabine ameliorates obesity-related insulin resistance by modulating macrophage polarization
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作者信息
1. 首都医科大学附属北京康复医院内分泌科,北京 100144
2. 解放军总医院第一医学中心内分泌科,北京 100853
3. 首都医科大学附属北京康复医学院,北京 100144
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摘要
背景 脂肪组织巨噬细胞(adipose tissue macrophages,ATMs)在介导肥胖诱导的胰岛素抵抗中起关键作用.体外实验发现,地西他滨可以调节巨噬细胞极化,至于其在ATMs以及肥胖相关胰岛素抵抗中的作用尚不明确.目的 利用体内、体外模型,检测地西他滨是否可以调节ATMs向M2极化,减轻肥胖相关的胰岛素抵抗.方法 高脂喂养制作胰岛素抵抗小鼠模型,通过胰岛素抵抗指数(homeostasis model assessment of insulin resistance,HOMA-IR)、腹腔胰岛素耐量试验、Western blot检测地西他滨对肥胖小鼠胰岛素敏感性的影响.提取小鼠脂肪组织,检测脂肪组织炎症水平;采用免疫荧光染色、流式细胞分析检测ATMs数量及表型的变化.体外研究中,将 3T3-L1脂肪细胞诱导为脂肪细胞,随机分为对照组、M1组、M2组,分别与PBS、LPS+IFN-γ刺激的巨噬细胞、地西他滨处理后巨噬细胞共培养,Western blot检测脂肪细胞PI3K和p-AKT的表达.结果 地西他滨处理后,肥胖小鼠的空腹胰岛素和HOMA-IR下降(P＜0.05),脂肪组织、肝组织和肌肉组织的胰岛素敏感性均得到改善(P＜0.05).与肥胖组相比,地西他滨处理后脂肪组织炎症减轻,CD11c、iNOS(M1型巨噬细胞)表达下调,CD206、Arg-1(M2型巨噬细胞)表达上调,差异均有统计学意义(P＜0.05).体外实验中,脂肪细胞与LPS+IFN-γ刺激的巨噬细胞共培养后PI3K、p-AKT表达下降,而与地西他滨处理后的巨噬细胞共培养,下降的PI3K、p-AKT表达显著上调(P＜0.05).结论 地西他滨可以减轻肥胖相关胰岛素抵抗,该效果可能源于地西他滨促进巨噬细胞向抑炎型M2型转化,减轻慢性炎症.
Abstract
Background The adipose tissue macrophages(ATMs)play a decisive role in mediating obesity-induced insulin resistance.Previous studies have found that low dose decitabine can promote macrophage polarization toward M2,but whether it can effectively reduce obesity-related insulin resistance is unclear.Objective To investigate whether decitabine can improve obesity-related insulin resistance by modulating ATMs toward M2 in vitro and in vivo.Methods Decitabine was given to mice on high fat diet by intraperitoneally injection once per day for 5 days.Two weeks later,glucose tolerance and insulin resistance were measured.Epididymal fat was extracted for analyzing inflammation and infiltrating macrophages in adipose tissue.In vitro,we examined the effects of decitabine-treated macrophages on insulin sensitivity in fully differentiated 3T3-L1 adipocytes.Results After treatment with dexamethasone,fasting insulin and HOMA-IR in obese mice decreased(P<0.05),and insulin sensitivity in adipose tissue,liver tissue,and muscle tissue improved(P<0.05).Compared with the obese group,treatment with dexamethasone reduced inflammation in adipose tissue,significantly downregulated the expression of CD11c and iNOS(M1 macrophages),and upregulated the expression of CD206 and Arg-1(M2 macrophages),with significant difference(P<0.05).In in vitro experiments,after adipocytes co-cultured with macrophages stimulated by LPS+IFN-γ,the expression of PI3K and p-AKT decreased,however,when adipocytes co-cultured with macrophages treated with dexamethasone,significant upregulation of the decreased expression of PI3K and p-AKT could be observed(P<0.05).Conclusion Decitabine may be a promising treatment for insulin resistance by regulating macrophage polarization and relieving chronic inflammation.
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