IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

Abstract

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.

Exercise training protects human and rodent β cells against endoplasmic reticulum stress and apoptosis

“…The IL6 myokine plays a role in the beneficial effect of serum from exercised humans Table 3). We identified 2 interesting candidates that signal through STAT3: IL-6 and IL-15 (30,37,38). Serum from subjects before and after training was incubated with IL6-neutralizing antibody before being added to EndoC-bH1 cells in the presence of cytokines or thapsigargin.…”

Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives

“…74,89 It has been reported that the signalling pathway for IL-15, induces hypoxia-inducible factor-1 α (HIF-1α) expression via JAK3/ STAT3 activation. In C2C12 myotubes, IL-15 increases basal and insulin-stimulated glucose uptake, GLUT4 translocation and GLUT4 mRNA levels.…”

“…In C2C12 myotubes, IL-15 increases basal and insulin-stimulated glucose uptake, GLUT4 translocation and GLUT4 mRNA levels. 74,89 It has been reported that the signalling pathway for IL-15, induces hypoxia-inducible factor-1 α (HIF-1α) expression via JAK3/ STAT3 activation. The activation of HIF-1α expression leads to an increase in GLUT4 translocation from the cytoplasm to the plasma membrane, accounting for the increase in glucose uptake in cultured myocytes in vitro and in isolated skeletal muscle ex vivo.…”

“…The activation of HIF-1α expression leads to an increase in GLUT4 translocation from the cytoplasm to the plasma membrane, accounting for the increase in glucose uptake in cultured myocytes in vitro and in isolated skeletal muscle ex vivo. 73,74,76,89 Although this line of evidence provides some insight into the molecular mechanism behind the stimulatory effect of IL-15 on insulin action, further studies are essential to firmly establish the unknown factors involved in the IL-15/JAK3/STAT3 signalling axis. Moreover, IL-15 has obvious relevance to understanding of, and to the potential treatment and/or prevention of, metabolic disorders, such as insulin resistance or diabetes.…”

“…Moreover, IL-15 has obvious relevance to understanding of, and to the potential treatment and/or prevention of, metabolic disorders, such as insulin resistance or diabetes. 73,74,76,89…”