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IL-15 Mediates Mitochondrial Activity through a PPARδ-Dependent-PPARα-Independent Mechanism in Skeletal Muscle Cells

机译:IL-15通过PPARδ依赖性PPARα依赖性机制介导骨骼肌细胞线粒体活性。

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摘要

Molecular mediators of metabolic processes, to increase energy expenditure, have become a focus for therapies of obesity. The discovery of cytokines secreted from the skeletal muscle (SKM), termed “myokines,” has garnered attention due to their positive effects on metabolic processes. Interleukin-15 (IL-15) is a myokine that has numerous positive metabolic effects and is linked to the PPAR family of mitochondrial regulators. Here, we aimed to determine the importance of PPARα and/or PPARδ as targets of IL-15 signaling. C2C12 SKM cells were differentiated for 6 days and treated every other day with IL-15 (100 ng/mL), a PPARα inhibitor (GW-6471), a PPARδ inhibitor (GSK-3787), or both IL-15 and the inhibitors. IL-15 increased mitochondrial activity and induced PPARα, PPARδ, PGC1α, PGC1β, UCP2, and Nrf1 expression. There was no effect of inhibiting PPARα, in combination with IL-15, on the aforementioned mRNA levels except for PGC1β and Nrf1. However, with PPARδ inhibition, IL-15 failed to induce the expression levels of PGC1α, PGC1β, UCP2, and Nrf1. Further, inhibition of PPARδ abolished IL-15 induced increases in citrate synthase activity, ATP production, and overall mitochondrial activity. IL-15 had no effects on mitochondrial biogenesis. Our data indicates that PPARδ activity is required for the beneficial metabolic effects of IL-15 signaling in SKM.
机译:为了增加能量消耗,代谢过程的分子介体已经成为肥胖疗法的焦点。骨骼肌(SKM)分泌的细胞因子被称为“肌动蛋白”,这一发现因其对代谢过程的积极作用而备受关注。白介素15(IL-15)是一种具有多种积极代谢作用的肌动蛋白,与线粒体调节剂的PPAR家族有关。在这里,我们旨在确定作为IL-15信号传导靶标的PPARα和/或PPARδ的重要性。 C2C12 SKM细胞分化6天,隔日用IL-15(100μng/ mL),PPARα抑制剂(GW-6471),PPARδ抑制剂(GSK-3787)或IL-15和抑制剂同时处理。 IL-15增加线粒体活性并诱导PPARα,PPARδ,PGC1α,PGC1β,UCP2和Nrf1表达。除PGC1β和Nrf1外,与IL-15联合使用对PPARα没有抑制作用。但是,在PPARδ抑制下,IL-15未能诱导PGC1α,PGC1β,UCP2和Nrf1的表达水平。此外,对PPARδ的抑制消除了IL-15诱导的柠檬酸合酶活性,ATP产生和总体线粒体活性的增加。 IL-15对线粒体的生物发生没有影响。我们的数据表明,PPARδ活性是SKM中IL-15信号转导的有益代谢作用所必需的。

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