Abstract

Background:

Exposure to coplanar polychlorinated biphenyls (PCBs) is linked to the development of insulin resistance. Previous studies suggested PCB126 alters muscle mitochondrial function through an indirect mechanism. Given that PCBs are stored in fat, we hypothesized that PCB126 alters adipokine secretion, which in turn affects muscle metabolism.

Objectives:

We determined a) the impacts of PCB126 exposure on adipocyte cytokine/adipokine secretion in vitro; b) whether adipocyte-derived factors alter glucose metabolism and mitochondrial function in myotubes when exposed to PCB126; and c) whether preestablished insulin resistance alters the metabolic responses of adipocytes exposed to PCB126 and the communication between adipocytes and myotubes.

Methods:

3T3-L1 adipocytes were exposed to PCB126 ($1–100\text{\hspace{0.17em}nM}$) in two insulin sensitivity conditions [insulin sensitive (IS) and insulin resistant (IR) adipocytes], followed by the measurement of secreted adipokines, mitochondrial function, and insulin-stimulated glucose uptake. Communication between adipocytes and myotubes was reproduced by exposing C2C12 myotubes or mouse primary myotubes to conditioned medium (CM) derived from IS or IR 3T3-L1 adipocytes exposed to PCB126. Mitochondrial function and insulin-stimulated glucose uptake were then determined in myotubes.

Results:

IR 3T3-L1 adipocytes treated with PCB126 had significantly higher adipokine (adiponectin, IL-6, MCP-1, $\text{TNF-}\mathrm{\alpha }$) secretion and lower mitochondrial function, glucose uptake, and glycolysis. However, PCB126 did not significantly alter these parameters in IS adipocytes. Altered energy metabolism in IR 3T3-L1 adipocytes was linked to lower phosphorylation of AMP-activated protein kinase (p-AMPK) and higher superoxide dismutase 2 levels, an enzyme involved in reactive oxygen species detoxification. Myotubes exposed to the CM from PCB126-treated IR adipocytes had lower glucose uptake, with no alteration in glycolysis or mitochondrial function. Interestingly, p-AMPK levels were higher in myotubes exposed to the CM of PCB126-treated IR adipocytes.

Discussion:

Taken together, these data suggest that increased adipokine secretion from IR adipocytes exposed to PCB126 might explain impaired glucose uptake in myotubes. https://doi.org/10.1289/EHP7058

中文翻译：

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体外模型中PCB126对脂肪与肌肉通讯的影响

摘要

背景：

共面多氯联苯（PCBs）的暴露与胰岛素抵抗的发展有关。先前的研究表明PCB126通过间接机制改变肌肉线粒体功能。鉴于多氯联苯储存在脂肪中，我们假设多氯联苯126改变了脂肪因子的分泌，进而影响了肌肉的新陈代谢。

目标：

我们确定a）PCB126暴露对体外脂肪细胞细胞因子/脂肪因子分泌的影响; b）暴露于PCB126时，脂肪细胞衍生因子是否会改变肌管中的葡萄糖代谢和线粒体功能；和Ç）是否预先建立胰岛素抗性涂改暴露于PCB126脂肪细胞的代谢反应和脂肪细胞和肌管之间的通信。

方法：

将3T3-L1脂肪细胞暴露于PCB126（$\mathrm{1个}–100\text{\hspace{0.17em}纳米}$）在两种胰岛素敏感性条件下（胰岛素敏感性（IS）和胰岛素抵抗（IR）脂肪细胞），然后测量分泌的脂肪因子，线粒体功能和胰岛素刺激的葡萄糖摄取。通过将C2C12肌管或小鼠原代肌管暴露于来源于暴露于PCB126的IS或IR 3T3-L1脂肪细胞的条件培养基（CM），可以再现脂肪细胞与肌管之间的通讯。然后在肌管中测定线粒体功能和胰岛素刺激的葡萄糖摄取。

结果：

经PCB126处理的IR 3T3-L1脂肪细胞的脂肪因子（脂联素，IL-6，MCP-1， $\text{肿瘤坏死因子}\mathrm{\alpha }$）分泌和降低线粒体功能，葡萄糖摄取和糖酵解。但是，PCB126并未显着改变IS脂肪细胞中的这些参数。IR 3T3-L1脂肪细胞中能量代谢的改变与AMP活化蛋白激酶（p-AMPK）的磷酸化水平降低和超氧化物歧化酶2（一种参与活性氧解毒的酶）水平较高有关。经PCB126处理的IR脂肪细胞暴露于CM的肌管具有较低的葡萄糖摄取，且糖酵解或线粒体功能无变化。有趣的是，在暴露于PCB126处理的IR脂肪细胞的CM的肌管中，p-AMPK水平较高。

讨论：

综上所述，这些数据表明，暴露于PCB126的IR脂肪细胞的脂肪因子分泌增加可能是肌管中葡萄糖摄取受损的原因。https://doi.org/10.1289/EHP7058