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 aforementionedmRNA levels except for PGC1𝛽 andNrf1.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.
Thornton SM, Krolopp JE, Abbott MJ. IL-15 mediates mitochondrial activity through a PPARδ-dependent-PPARα-independent mechanism in skeletal muscle cells. PPAR Research. 2016;2016:5465804. doi:10.1155/2016/5465804.
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