Interleukin-15 as a myokine: mechanistic insight into its effect on skeletal muscle metabolism

Interleukin (IL)-15 is a cytokine with important immunological functions. It is highly expressed in skeletal muscle and is believed to be a myokine, a hypothesis supported by the rapid increase in circulating levels of IL-15 in response to exercise. Treatment with high doses of IL-15 results in metabolic adaptations such as improved insulin sensitivity and whole-body fatty acid oxidation and protection from high-fat-diet-induced obesity and insulin resistance. IL-15 secreted by contracting muscle may therefore act as an endocrine factor to improve adiposity and energy metabolism in different tissues. Most studies have used supraphysiological doses of IL-15 that do not represent circulating IL-15 in response to exercise. However, evidence shows that IL-15 levels are higher in muscle interstitium and that IL-15 might improve muscle glucose homeostasis and oxidative metabolism in an autocrine/paracrine manner. Nevertheless, how IL-15 signals in skeletal muscle to improve muscle energy metabolism is not understood completely, especially because the absence of the α subunit of the IL-15 receptor (IL-15Rα) results in a phenotype similar to that of overexpressing/oversecreting IL-15 in mice. In this article, we review the literature to propose a model for the regulation of IL-15 by the soluble form of IL-15Rα to explain why some findings in the literature seem, at first glance, to be contradictory.