title: IL-15 Mediates Mitochondrial Activity through a PPARδ-Dependent-PPARα-Independent Mechanism in Skeletal Muscle Cells.
abstract: 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 PPARαand/or PPARδas 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 PPARαinhibitor (GW-6471), a PPARδinhibitor (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 PGC1βand Nrf1. However, with PPARδinhibition, IL-15 failed to induce the expression levels of PGC1α, PGC1β, UCP2, and Nrf1. Further, inhibition of PPARδabolished 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 PPARδactivity is required for the beneficial metabolic effects of IL-15 signaling in SKM.
authors.affiliation: Department of Health Science and Kinesiology, Crean College of Health and Behavioral Sciences, Chapman University, Orange, CA, USA.
authors.forename: Shantaé M
authors.identifier: 0000-0001-5417-4346
authors.initials: SM
authors.lastname: Thornton
authors.affiliation: Department of Health Science and Kinesiology, Crean College of Health and Behavioral Sciences, Chapman University, Orange, CA, USA.
authors.forename: James E
authors.identifier: 0000-0003-2619-394X
authors.initials: JE
authors.lastname: Krolopp
authors.affiliation: Department of Health Science and Kinesiology, Crean College of Health and Behavioral Sciences, Chapman University, Orange, CA, USA; Department of Biological Sciences, Human and Evolutionary Biology Section, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA.
authors.forename: Marcia J
authors.identifier: 0000-0003-2558-8093
authors.initials: MJ
authors.lastname: Abbott