胃旁路手术调节胰岛素抵抗机制的研究

Mechanism of glucose homeostasis regulation by Roux- en- Y gastric bypass

目的研究Roux—en—Y胃旁路手术（RYGB）对高脂饮食诱导的肥胖小鼠（DIO）胰岛素抵抗的调节机制。方法将C57BL／6、H-2b小鼠随机分为胃旁路术组、假手术组和对照组。记录各组小鼠术后脂肪沉积及胰岛素敏感性；生化法检测血浆与脂肪组织细胞因子含量；荧光报告分析法检测荧光素活性；Westernblot法检测组织核因子（NF）-KB及c-Jun氨基末端激酶（JNK）／c-Jun表达量；流式细胞仪检测组织巨噬细胞以及T细胞亚型。结果RYGB能有效改善小鼠的肥胖及胰岛素抵抗。与对照组DIO小鼠比较，RYGB小鼠的血浆胰岛素[（4．1±1．1）μg／L]及瘦素量均相应减少；此外RYGB能稳定白脂肪以及肝脏中的脂联素水平，单核细胞趋化因子-1（MCP-1）及白细胞介素（IL）-6表达也显著降低；RYGB能抑制高脂饮食（HFD）引起的白脂肪及肝脏组织中特异性的NF-κB及JNK／c—Jun信号通路激活；RYGB还能抑制肝脏和白脂肪中巨噬细胞M1亚群产生，促进M2亚群分化，调节CD4＋及CD8＋T细胞的浸润，增加调节性T细胞比例。结论DIO小鼠模型中，RYGB改善肥胖和胰岛素抵抗与早期炎症调节反应相关。

Objective We tested early immunological events of Roux - en - Y gastric bypass （RYGB） , an effective approach for the improvement of glucose homeostasis, using the high - fat diet - in- duced obese （DIO） mouse model. Methods RYGB was performed with DIO mice that were divided into the following groups： RYGB, pair -feeding with sham surgery （SHAM -PF） , and control （untreated DIO mice）. We analyzed adiposity, insulin sensitivity, plasma and tissue cytokines and adipokines, tissue nu- clear factor （NF） -KB and c-Jun N- terminal kinase （JNK）/c -Jun activation and tissue macrophage and T cell subsets. Results We found that RYGB resulted in sustained improvement of adiposity and insu- lin sensitivity. Plasma insulin and leptin levels were increased in untreated DIO mice and reduced in RYGB mice [ （4. 1± 1.1 ）ug/L ]. RYGB maintained plasma adiponectin levels and inhibited monocyte chemo- tactic protein- 1 （MCP- 1 ） and interleukin （IL） -6 in white adipose tissue （WAT） and liver. RYGB inhibited tissue specific NF - KB activation in WAT and muscle and the JNK/c -Jun signaling pathway in the liver and WAT at first week post - surgery, suggesting that high fat diet （HFD） stimulated a tissue spe- cific activation of NF -κB and JNK/c - Jun pathways. RYGB also inhibited M1 - like differentiation and enhanced M2 -like population, regulated CD4＋and CD8＋ T cell infiltration and promoted regulatory T （Treg） cell generation in the liver and WAT at the same time point. Conclusion The data demonstrate that the improvement in insulin resistance following RYGB is associated with the early regulation of inflam- matory reactions in the mouse DIO model.