新一期的《糖尿病学术前沿》又和大家见面了。本期学术前沿相关内容如下：
关注双酚A（BPA）等内分泌干扰物：介导免疫调节代谢机制探讨
双酚A（BPA）等内分泌干扰物可能通过介导免疫系统来影响代谢健康，本期将分享相关内容。
研究表明，内分泌干扰物（EDCs）可能通过介导免疫系统来影响代谢健康，该领域的研究可能为未来代谢性疾病的预防和治疗提供新的思路。本期将分享相关内容。
一、什么是内分泌干扰物（EDCs）？
代谢紊乱疾病如2型糖尿病和肥胖症的发病率逐年增加1, 2。造成这一现象的原因是多方面的。除却已知的营养过剩和不良生活方式这两个主要因素，暴露于环境中的各种化学物质可能也是一个重要原因3-7。由于这些外源性化学物质可从多个方面破坏内分泌激素的正常作用，因此也被称为内分泌干扰物（EDCs）8,9。
EDCs种类多且复杂,按其来源可分为天然和人工合成化合物两大类。它们会增加糖尿病和肥胖的风险，尤以双酚A（BPA）10和邻苯二甲酸酯11这两种物质为甚。
研究表明，ECDs可能通过介导免疫系统来影响代谢健康12,13。更好地理解EDCs的免疫调节作用，将有助于改善代谢功能，并有助于减轻由生活环境所致的糖尿病和肥胖的负担。
二、免疫系统如何调节代谢健康？
代谢健康的免疫调节近年来受到了广泛关注。固有免疫系统（自然杀伤细胞、肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞和巨噬细胞的吞噬细胞，如树突状细胞和中性粒细胞）和适应性免疫应答系统（CD8+和CD4+ T淋巴细胞，以及B淋巴细胞）都在代谢疾病进展中发挥关键影响。
在脂肪组织中，这两套免疫系统之间的交互作用已被广泛探讨14。 肥胖时肥大的脂肪细胞产生趋化性脂肪细胞因子和趋化因子，如单核细胞趋化蛋白-1（MCP-1）和白三烯B4 （LTB4）。此外，脂肪组织会释放促炎性细胞因子，如肿瘤坏死因子α（TNF-α）、γ-干扰素（IFN-γ）和白细胞介素17（IL-17），促进脂肪组织巨噬细胞向促炎性M1巨噬细胞转化15。脂肪细胞、固有免疫系统和适应性免疫系统的交互作用造就了脂肪组织的促炎症环境。
与之类似，在胰岛素抵抗和2型糖尿病中，代谢敏感组织（胰腺、肝脏、骨骼肌、肠和血管）中固有免疫和适应性免疫的交互作用，打破了促炎和抗炎的平衡，最终干扰了代谢健康16。
与代谢紊乱相关的细胞内促炎信号通路共有三条，分别是核因子kB/kB激酶抑制剂通路（NFκB)/ IKκB）、c-Jun氨基末端激酶/激活蛋白-1通路（JNK/AP1），以及炎性小体通路17, 18（图2）。这三条通路经常交叠作用。促炎信号通路一旦激活，则会增加胰岛素受体底物1/2（IRS1 / 2）磷酸化以及炎症基因的转录，从而增加胰岛素抵抗17, 18（图1）。
与促炎信号通路相反，由G蛋白偶联受体120（GPR120）、雌激素受体α（ERα）和白介素10（IL-10）激活的抗炎信号通路则可抑制胰岛素抵抗17-19 (图1)。促炎和抗炎因子水平的平衡决定着炎症的大小量级，并对维持代谢平衡起着至关重要的作用。
图1. 胰岛素抵抗的炎症相关信号通路
三、EDCs对免疫系统的影响机制
EDCs对免疫系统的影响机制可能是多方面的。其中已发现对维持代谢平衡有重要作用的机制有以下四种（图2）。
1. 受体。EDCs通过与受体结合来影响免疫系统，如雌激素受体（ERS）、雌激素相关受体（ERR）、过氧化物酶体增殖物激活受体γ（PPARγ）、Toll样受体（TLR）和NOD样受体（NLRs）20-23。
2. 肠道菌群。肠道菌群的个体差异很大，不同的肠道菌群会带来不同的EDCs代谢24。综合以往的研究，EDC会损伤正常的肠道菌群并对代谢健康带来不利的影响25-27。
3. 氧化应激。体内体外研究都显示EDCs可以增加肾脏、胰腺和肝脏的内质网应激28-31。线粒体功能障碍和内质网应激与氧化应激增强和代谢紊乱相关。
4. 昼夜节律破坏。昼夜节律紊乱会损害体内的代谢平衡，同样，生活方式的因素，如睡眠/唤醒模式、轮班工作、时差等导致的昼夜节律紊乱，均会改变免疫系统功能。最近的研究表明，EDCs可以扰乱昼夜节律性32-34。
图2. EDC作用于免疫系统从而导致代谢紊乱的可能路径
免疫功能障碍增加了糖尿病和肥胖等各种代谢紊乱的风险，而无处不在的EDCs又使风险进一步加剧。在未来针对EDC领域的研究中，应把EDC对免疫系统的作用考虑在内，从而找到新的针对环境引起的代谢疾病的预防和治疗方法。
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