Krolopp James E, Thornton Shantaé M, Abbott Marcia J
Department of Health Sciences and Kinesiology, Crean College of Health and Behavioral Sciences, Chapman University Orange, CA, USA.
Department of Health Sciences and Kinesiology, Crean College of Health and Behavioral Sciences, Chapman UniversityOrange, CA, USA; Department of Biological Sciences, Human and Evolutionary Biology Section, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern CaliforniaLos Angeles, CA, USA.
Front Physiol. 2016 Dec 20;7:626. doi: 10.3389/fphys.2016.00626. eCollection 2016.
Myokines are specialized cytokines that are secreted from skeletal muscle (SKM) in response to metabolic stimuli, such as exercise. Interleukin-15 (IL-15) is a myokine with potential to reduce obesity and increase lean mass through induction of metabolic processes. It has been previously shown that IL-15 acts to increase glucose uptake in SKM cells. However, the downstream signals orchestrating the link between IL-15 signaling and glucose uptake have not been fully explored. Here we employed the mouse SKM C2C12 cell line to examine potential downstream targets of IL-15-induced alterations in glucose uptake. Following differentiation, C2C12 cells were treated overnight with 100 ng/ml of IL-15. Activation of factors associated with glucose metabolism (Akt and AMPK) and known downstream targets of IL-15 (Jak1, Jak3, STAT3, and STAT5) were assessed with IL-15 stimulation. IL-15 stimulated glucose uptake and GLUT4 translocation to the plasma membrane. IL-15 treatment had no effect on phospho-Akt, phospho-Akt substrates, phospho-AMPK, phospho-Jak1, or phospho-STAT5. However, with IL-15, phospho-Jak3 and phospho-STAT3 levels were increased along with increased interaction of Jak3 and STAT3. Additionally, IL-15 induced a translocation of phospho-STAT3 from the cytoplasm to the nucleus. We have evidence that a mediator of glucose uptake, HIF1α, expression was dependent on IL-15 induced STAT3 activation. Finally, upon inhibition of STAT3 the positive effects of IL-15 on glucose uptake and GLUT4 translocation were abolished. Taken together, we provide evidence for a novel signaling pathway for IL-15 acting through Jak3/STAT3 to regulate glucose metabolism.
肌动蛋白是一类特殊的细胞因子，由骨骼肌（SKM）分泌，以响应代谢刺激，如运动。白细胞介素-15（IL-15）是一种肌动蛋白，具有通过诱导代谢过程来减轻肥胖和增加瘦体重的潜力。先前的研究表明，IL-15可促进SKM细胞摄取葡萄糖。然而，协调IL-15信号与葡萄糖摄取之间联系的下游信号尚未得到充分探索。在此，我们使用小鼠SKM C2C12细胞系来研究IL-15诱导的葡萄糖摄取变化的潜在下游靶点。分化后，C2C12细胞用100 ng/ml的IL-15处理过夜。通过IL-15刺激评估与葡萄糖代谢相关的因子（Akt和AMPK）以及IL-15的已知下游靶点（Jak1、Jak3、STAT3和STAT5）的激活情况。IL-15刺激葡萄糖摄取并使GLUT4转运至质膜。IL-15处理对磷酸化Akt、磷酸化Akt底物、磷酸化AMPK、磷酸化Jak1或磷酸化STAT5无影响。然而，在IL-15作用下，磷酸化Jak3和磷酸化STAT3水平升高，同时Jak3与STAT3的相互作用增强。此外，IL-15诱导磷酸化STAT3从细胞质转位至细胞核。我们有证据表明，葡萄糖摄取的介质HIF1α的表达依赖于IL-15诱导的STAT3激活。最后，抑制STAT3后，IL-15对葡萄糖摄取和GLUT4转运的积极作用被消除。综上所述，我们为IL-15通过Jak3/STAT3调节葡萄糖代谢的新信号通路提供了证据。
