Interleukin-15 as a myokine: Mechanistic insight into its effect on skeletal muscle metabolism
Abstract
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.
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IL-15 augments PPARδ and PGC-1α activity, favoring mitochondrial biogenesis and fatty acid oxidation.
“and augments PPARδ and PGC-1α activity, favoring mitochondrial biogenesis and FAO [84,91,126]”
In obese/T2DM subjects, soluble IL-15Rα is released in greater amounts, impairing upregulation of skeletal muscle oxidative metabolism or lipolysis in white adipose tissue.
“In obese/T2DM subjects, soluble IL-15Rα is released in greater amounts, impairing upregulation of SkM oxidative metabolism or lipolysis in WAT [84].”
Some exercise-induced factors have direct insulin-sensitizing effects in target tissues, independently of their effect on inflammation, such as irisin, IL-6, IL-15, METRNL, BAIBA, and FGF21.
“Importantly, some exercise-induced factors have also been shown to have direct insulin-sensitizing effects in target tissues, independently of their effect on inflammation, such as irisin [56], IL-6 [122], IL-15 [84], METRNL [274], BAIBA [112], and FGF21 [154] (10).”
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“Importantly, some exercise-induced factors have also been shown to have direct insulin-sensitizing effects in target tissues, independently of their effect on inflammation, such as irisin [56], IL-6 [122], IL-15 [84], METRNL [274], BAIBA [112], and FGF21 [154] (10).”
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- Authors
- Nadeau, L., & Aguer, C.
- Affiliations
- University of Ottawa (CA)
- ORCID
- Aguer, Céline
- Venue
- Applied Physiology Nutrition and Metabolism
- Publisher
- Canadian Science Publishing
- Published
- 2019-03
- Volume
- 44
- Issue
- 3
- Pages
- 229-238
- ISSN
- 1715-5312 (ISSN-L)
- 1715-5320
- OpenAlex
- W2890580671
- Cited by
- 83
- References
- 90
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 11 · 2023: 14 · 2022: 15 · 2021: 7 · 2020: 11 · 2019: 4 · 2018: 1
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Applied Physiology, Nutrition, and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- IL-15, myokines, skeletal muscle metabolism, IL-15 receptor alpha, autocrine and paracrine signaling, physical activity, insulin sensitivity, fatty acid oxidation, glucose homeostasis, oxidative metabolism, obesity, energy metabolism, cytokines
- MeSH terms
- Animals, Energy Metabolism, Glucose, Humans, Insulin Resistance, Exercise, Muscle, Skeletal, Interleukin-15, PPAR gamma, Adiposity, Lipid Metabolism, Mice, Interleukin-15 Receptor alpha Subunit
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