The prevalence of type 2 diabetes, obesity and their various comorbidities have continued to rise. In skeletal muscle lipotoxicity is well known to be a contributor to the development of insulin resistance. Here it was examined if the small molecule adiponectin receptor agonist AdipoRon mimicked the effect of adiponectin to attenuate palmitate induced reactive oxygen species (ROS) production and cell death in L6 skeletal muscle cells. L6 cells were treated ±0.1 mM PA, and ± AdipoRon, then assays analyzing reactive oxygen species (ROS) production and cell death, and intracellular and extracellular levels of sphingosine-1 phosphate (S1P) were conducted. To determine the mechanistic role of S1P gain (using exogenous S1P or using THI) or loss of function (using the SKI-II) were conducted. Using both CellROX and DCFDA assays it was found that AdipoRon reduced palmitate-induced ROS production. Image-IT DEAD, MTT and LDH assays all indicated that AdipoRon reduced palmitate-induced cell death. Palmitate significantly increased intracellular accumulation of S1P, whereas in the presence of AdipoRon there was increased release of S1P from cells to extracellular medium. It was also observed that direct addition of extracellular S1P prevented palmitate-induced ROS production and cell death, indicating that S1P is acting in an autocrine manner. Pharmacological approaches to enhance or decrease S1P levels indicated that accumulation of intracellular S1P correlated with enhanced cell death. This data indicates that increased extracellular levels of S1P in response to adiponectin receptor activation can activate S1P receptor-mediated signaling to attenuate lipotoxic cell death. Taken together these findings represent a possible novel mechanism for the protective action of adiponectin.

中文翻译：

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脂联素-S1P自分泌轴可保护骨骼肌细胞免受棕榈酸酯诱导的细胞死亡。

2型糖尿病，肥胖症及其各种合并症的患病率持续上升。众所周知，在骨骼肌中，脂毒性是胰岛素抵抗发展的原因。在这里检查了小分子脂联素受体激动剂AdipoRon是否模仿了脂联素减弱棕榈酸诱导的活性氧（ROS）产生和L6骨骼肌细胞死亡的作用。用±0.1 mM PA和±AdipoRon处理L6细胞，然后分析活性氧（ROS）产生和细胞死亡，并进行细胞内和细胞外神经鞘氨醇-1磷酸酯（S1P）水平的测定。为了确定S1P获得（使用外源S1P或使用THI）或功能丧失（使用SKI-II）的机械作用。通过使用CellROX和DCFDA分析，发现AdipoRon减少了棕榈酸酯诱导的ROS产生。Image-IT DEAD，MTT和LDH分析均表明AdipoRon减少了棕榈酸酯诱导的细胞死亡。棕榈酸酯显着增加了S1P在细胞内的积累，而在AdipoRon存在的情况下，S1P从细胞向细胞外培养基的释放增加。还观察到，直接添加细胞外S1P阻止了棕榈酸酯诱导的ROS产生和细胞死亡，这表明S1P以自分泌方式起作用。增强或降低S1P水平的药理学方法表明，细胞内S1P的积累与细胞死亡增强相关。该数据表明响应脂联素受体激活而增加的细胞外S1P水平可以激活S1P受体介导的信号传导，从而减轻脂毒性细胞死亡。总之，这些发现代表了脂联素保护作用的可能新机制。