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Oversecretion of interleukin-15 from skeletal muscle reduces adiposity
Open accessAbstract
Obesity is a risk factor for development of insulin resistance, type 2 diabetes, cardiovascular disease, osteoarthritis, and some forms of cancer. Many of the adverse health consequences of excess fat deposition are caused by increased secretion of proinflammatory adipokines by adipose tissue. Reciprocal muscle-to-fat signaling factors, or myokines, are starting to be identified. Interleukin-15 (IL-15) is a cytokine that is highly expressed in muscle tissue and that, on the basis of cell culture experiments, has been proposed to act as a circulating myokine that inhibits adipose tissue deposition. To test this hypothesis in vivo, two lines of transgenic mice that overexpressed IL-15 mRNA and protein in skeletal muscle tissue were constructed. By substitution of the inefficient native IL-15 signal peptide with a more efficient signal peptide, one of the transgenic mouse lines also exhibited elevated secretion of IL-15 in the circulation. Overexpression of IL-15 in muscle tissue without secretion in the bloodstream resulted in no differences in body composition. Elevated circulating levels of IL-15 resulted in significant reductions in body fat and increased bone mineral content, without appreciably affecting lean body mass or levels of other cytokines. Elevated circulating levels of IL-15 also inhibited adiposity induced by consumption of a high-fat/high-energy diet in male, but not female, transgenic mice. Female mice with elevated serum IL-15 exhibited increased deposition of lean body mass on a low-fat/low-energy diet and a high-fat/high-energy diet. These findings indicate that muscle-derived circulating IL-15 can modulate adipose tissue deposition and support addition of IL-15 to the growing list of potential myokines that are increasingly being implicated in regulation of body composition.
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“as exemplified in a murine model overexpressing IL-15 in which the percentage of visceral fat mass, measured by DEXA, was approximately half when compared with controls [88].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [88]
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“Interleukin-15 exerts local anabolic/anti-catabolic effects [10] and increases glucose uptake, thus inhibiting lipid deposition [10, 11].”
From β-hydroxy-β -methylbutyrate supplementation benefits the effects of resistance training on body fat reduction via increased irisin expression in white adipose tissue (2021) · cites this paper as [11]
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“The ability of IL-15 to act on muscle- adipose tissue crosstalk was investigated by the same group, showing IL-15 overexpression in relation to reduced adiposity.”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Quinn et al., 2009
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“Only the group that had the increased levels of IL-15 from the muscle in circulation had a reduction in adiposity due to the greater targeting of this substrate for energy generation (Quinn et al., 2009).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Quinn et al., 2009
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InfluentialMyokine Expression in Muscle and Myotubes in Response to Exercise Stimulation
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“IL-15 and leukocyte-inducing factor (LIF) have been speculated to regulate muscle cell growth and satellite cell proliferation (7,18), with IL-15 playing a potential role in adipose tissue lipolysis (33).”
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“Humoral factors produced by muscle cells, such as interleukin (IL)-6 and IL-15, which are secreted during exercise and involved in bone hypertrophy [51,52]; irisin, which promotes osteoblast differentiation [53,54]; and myostatin (growth differentiation factor-8; GDF-8, etc.”
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“Skeletal muscle is a principal depot for both IL-15 mRNA and protein, which may be translated or released upon appropriate physiological stimuli (6).”
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“In oxidative (soleus) muscle, parallel reductions in transcript and protein were observed for IL-15, VEGF, sIL1RI, sVEGFR1, sVEGFR2, and sgp130, whereas parallel increases were only observed for CCL12 and TIMP-1.”
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Interleukin-15 Treatment Induces Weight Loss Independent of Lymphocytes
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IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity
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“GH1, a hormone secreted by the anterior lobe of the pituitary gland that stimulates lipolysis in adipose tissue and free fatty acid oxidation in the liver,(37) presented the strongest upregulation, followed by other lipolytic factors such as IL-6 and IL15.(38,39) IL-6 is upregulated in obese individuals and patients w…”
BackgroundIL-15/sIL-15Rα gene transfer induces weight loss and improves glucose homeostasis in obese mice
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Muskelaktivität: Prägung des ZNS und endokrine Funktion
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“Alterations in adipose tissue composition can also be affected by myokines (Quinn et al. 2009).”
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“…positive relationship between post-exercise IL-15 concentrations and lean mass is unsurprising given IL-15 is one of the most abundant myokines found in skeletal muscle and skeletal muscle synthesis influences fat oxidation (Quinn, 2008; Quinn et al., 1995; Quinn et al., 2002; Quinn et al., 2009).”
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“These mice are also leaner and are resistant to high-fat dietinduced obesity, suggesting that IL-15 release from skeletal muscle can have endocrine effects, although, sex-specific differences in body composition were observed (40).”
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IL-15Rα deficiency leads to mitochondrial and myofiber differences in fast mouse muscles
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“Recent work has demonstrated that genetic manipulation of IL-15 and IL-15Rα in vivo in the absence of exercise training results in a more oxidative muscle phenotype with functional changes similar to fatigue resistant skeletal muscles [6-8].”
BackgroundCirculating irisin levels and muscle FNDC5 mRNA expression are independent of IL-15 levels in mice
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“Famous examples for such myokines are interleukin-15 (Quinn et al., 2009) and the controversially discussed irisin (Albrecht et al., 2015; Raschke et al., 2013).”
BackgroundIdentification of CCL5/RANTES as a novel contraction-reducible myokine in mouse skeletal muscle
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“Interleukin-15 is an anabolic factor in muscle growth, also presents a negative effect to the fat mass [29].”
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Barber, T. M., Kabisch, S., Pfeiffer, A. F. H., & Weickert, M. O. (2025) · Metabolites · doi:10.3390/metabo15020085 · Cited by 19
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“The first myokine to be identified was myostatin (a potent inhibitor of myocyte proliferation), with others being later identified, including irisin (which induces browning of white adipose tissue), IL8 (which induces angiogenesis), and IL15 (which reduces adipose tissue) (89-91).”
BackgroundCrosstalk between bone and muscle in chronic kidney disease
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“Finally, higher circulating IL-15 levels correlate with a reduction in body fat and increased bone mineral content in mice (105).”
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Lombardi, G., Sansoni, V., & Banfi, G. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2017.07.11 · Cited by 17
“Although considered a proinflammatory cytokine, the negative correlation of circulating IL-15 with obesity, WAT mass and T2DM suggest a role as a myokine (94).”
BackgroundTamura, K., Goto‐Inoue, N., Miyata, K., Furuichi, Y., FUJII, N. L., & Manabe, Y. (2020) · PLoS ONE · doi:10.1371/journal.pone.0237095 · Cited by 15
“Moreover, skeletal muscle-specific overexpression of IL-15 inhibits adipose tissue deposition [9].”
BackgroundIs Tissue Cross-Talk Important in Cancer Cachexia?
Johns, N., Greig, C. A., & Fearon, K. C. H. (2012) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.v17.i3.40 · Cited by 15
Anderson, B. G., & Quinn, L. S. (2016) · Endocrinology · doi:10.1210/en.2015-1746 · Cited by 14
Dolly, A., Lecomte, T., Bouché, O., Borg, C., Terrebonne, É., Douillard, J., Chautard, R., Raoul, W., Ternant, D., Léger, J., et al. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.02.017 · Cited by 14
“Conversely, secretion of IL-15 by muscle seems to increase bone mineral con-tent [24].”
BackgroundHormonal, immune, and oxidative stress responses to blood flow‐restricted exercise
Hjortshoej, M. H., Aagaard, P., Storgaard, C. D., Juneja, H., Lundbye‐Jensen, J., Magnusson, S. P., & Couppé, C. (2023) · Acta Physiologica · doi:10.1111/apha.14030 · Cited by 13
Creatine kinase is associated with reduced inflammation in a general population: The Tromsø study
Bekkelund, S. I., & Johnsen, S. H. (2018) · PLoS ONE · doi:10.1371/journal.pone.0198133 · Cited by 13
Sánchez-Jiménez, R., Cerón, E., Bernal-Alcántara, D. A., Castillejos-López, M. D. J., González-Trujano, E., Negrete-García, M. C., & Alvarado‐Vásquez, N. (2018) · Tuberculosis · doi:10.1016/j.tube.2018.06.009 · Cited by 13
Effect of Eccentric Exercise on Metabolic Health in Diabetes and Obesity
Szűcs, G., Pipicz, M., Szabó, M. R., Csont, T., Török, L., & Csonka, C. (2023) · Sports Medicine - Open · doi:10.1186/s40798-023-00596-2 · Cited by 12
“Besides the anabolic effects, skeletal muscle-derived circulating IL-15 seems to reduce lipid accumulation in adipocytes; therefore, it is proposed to be a possible link in the exercise-mediated muscle-fat crosstalk [100, 101].”
BackgroundLim, J. Y., & Kim, E. (2023) · Metabolites · doi:10.3390/metabo13090979 · Cited by 13
LeDrew, M., Sadri, P., Peil, A., & Farahnak, Z. (2025) · Nutrients · doi:10.3390/nu17172758 · Cited by 13
“IL-15 also functions as a circulating myokine that helps reduce fat storage in the body by inhibiting adipose tissue deposition [79].”
InfluentialSerum interleukin 15 in anorexia nervosa: Comparison to normal weight and obese girls
Roczniak, W., Mikołajczak, A., Świętochowska, E., Ostrowska, Z., Ziora, K. T., Balcerowicz, S., Górska-Flak, K., Milan, M., & Oświęcimska, J. M. (2019) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2019.1583370 · Cited by 11
“…vitro and in vivo studies performed so far in animal models (Carb o et al. 2001; Almendro et al. 2006; Busquets et al. 2006; Almendro et al. 2008; Quinn et al. 2009; Barra et al. 2012; Barra et al. 2014; Oh et al. 2016), the beneficial properties of IL-15 for preventing excessive accumulation of…”
BackgroundInfluentialYoshida, S., Fujimoto, T., Takahashi, T., Sugimoto, K., Akasaka, H., Tanaka, M., Huang, Y., Yasunobe, Y., Xie, K., Ohnishi, Y., et al. (2022) · Experimental Physiology · doi:10.1113/ep090205 · Cited by 11
Myokines: Do they really exist?
Manabe, Y., Miyatake, S., & Takagi, M. (2012) · The Journal of Physical Fitness and Sports Medicine · doi:10.7600/jpfsm.1.51 · Cited by 11
Exercise training remodels inter-organ endocrine networks
Ahn, C., Hevener, A. L., Goodyear, L. J., Bodine, S. C., Esser, K. A., Seldin, M. M., & Sparks, L. M. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102219 · Cited by 9
“IL15 is a well-characterized exercise-inducible myokine that promotes triglyceride breakdown (i.e., lipolysis) and fatty acid oxidation in adipose tissue [19,20].”
Therapeutic strategies to modulate gut microbial health: Approaches for sarcopenia management.
Das, S., Preethi, B., Kushwaha, S., & Shrivastava, R. (2024) · PubMed · doi:10.14670/hh-18-730 · Cited by 13
The Dual Role of Myokines in Fatigue Associated with Inflammatory Joint Diseases
Chmielewski, G., Kuna, J., Jaśkiewicz, Ł., Knapik, M., Mikiewicz, M., Majewski, M. S., & Krajewska–Włodarczyk, M. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s545914 · Cited by 9
Szabó, M. R., Csont, T., & Csonka, C. (2023) · Physiology International · doi:10.1556/2060.2023.00198 · Cited by 11
Jawkar, S., & Nongthomba, U. (2020) · The International Journal of Developmental Biology · doi:10.1387/ijdb.190333un · Cited by 9
“Evidence for regulation of biological processes by myokines in non-muscle cells came through multiple studies (Bouzakri et al., 2011; Quinn et al., 2008; Seldin et al., 2012; Zeng et al., 2010).”
BackgroundDiverse Abnormal Body Composition Phenotypes: Interaction Between Muscle, Fat, and Bone
Kim, T. N. (2015) · The Korean Journal of Obesity · doi:10.7570/kjo.2015.24.1.9 · Cited by 8
“저항성 운동 시에 근육조직에 IL-15도 높게 발현되며, IL-15를 과발현시킨 트랜스제닉 마우스는 지방량은 감소하고 골량은 증가하는 것으로 나타났다.(57,58) 한편, 운동 시 간세포에서 분비가 증가되는 follistatin은 myostatin의”
A systematic review of “myokines and metabolic regulation”
Leon‐Ariza, H. H., Mendoza-Navarrete, M. P., Maldonado-Arango, M. I., & Botero‐Rosas, D. A. (2018) · Apunts Sports Medicine · doi:10.1016/j.apunts.2018.09.003 · Cited by 8
Loro, E., Jang, C., Quinn, W. J., Baur, J. A., Arany, Z. P., & Khurana, T. S. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01439 · Cited by 8
Zumbaugh, M. D., Yen, C., Bodmer, J. S., Shi, H., & Gerrard, D. E. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.682052 · Cited by 9
Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation
Saunders, A., Shim, Y. A., & Johnson, P. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302681 · Cited by 8
“The primers used were as follows: GAPDH: Forward 59-ACCACAGTCCATGCCATCAC-39, Reverse 59-CACCACCCTGTTGCTGTAGCC-39 (19); IL-7: Forward 59-GTGCCACATTAAAGACAAAGAAG-39, Reverse 59-GTTCATTATTCGGGCAATTACTATC-39 (20); IL-15: Forward 59-CAGCACTCTGTCTTCTAACAAGAA39, Reverse 59-TCTGTGAAGGTTTTCTCCTCC-39 (21); IL-15Ra: Forward 59GC…”
MethodEffects of interleukin-15 on autophagy regulation in the skeletal muscle of mice
Tanaka, M., Sugimoto, K., Akasaka, H., Yoshida, S., Takahashi, T., Fujimoto, T., Keyu, X., Yasunobe, Y., Yamamoto, K. I., Hirabayashi, T., et al. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00311.2023 · Cited by 7
Cell-cell crosstalk between fat cells and immune cells
Liu, J., & Chen, Y. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00024.2024 · Cited by 7
Pollak, N., Janežič, E. G., Šink, Ž., & Ugwoke, C. K. (2025) · Metabolites · doi:10.3390/metabo15090581 · Cited by 10
“IL-15 exhibits negative correlations with fat mass and may support local metabolic interactions by promoting PPAR-driven fatty acid oxidation and shifting the cytokine milieu toward a less inflammatory state [190,191].”
Obesity and type 2 diabetes as chronic inflammation: how does the cytokine evidence align?
Bhatia, K., Gupta, V. K., & Upadhyay, S. K. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1721206 · Cited by 15
“Its over-expression in muscle and increased levels in circulation reduces adiposity (201, 202).”
Health benefits of physical activity: What role does skeletal muscle-organ crosstalk play?
Powers, S. K., Goldstein, E. R., Lategan-Potgieter, R., Schrager, M. A., Skelton, M., & Demirel, H. A. (2025) · Sports Medicine and Health Science · doi:10.1016/j.smhs.2025.02.010 · Cited by 7
Gao, T., Liu, F., Ban, B., Hou, Y., Li, G., Jiang, M., Yang, Q., & Zhang, M. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.1035853 · Cited by 7
“The myokines secreted by muscles may regulate the bone mineral content, such IL-15 (28), IL8 (29) and irisin (30).”
BackgroundTHE ROLE OF MYOKINES INTERSTITIAL INTERACTION AND REGULATION OF METABOLISM: A REVIEW OF LITERATURE
Тамерланович, Ц. Т., White, Z. E., & Rozhinskaya, L. Y. (2016) · Osteoporosis and Bone Diseases · doi:10.14341/osteo2016128-34 · Cited by 7
Eckel, J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809518-8.00003-9 · Cited by 7
Interleukin 15 participates in Jagged1-induced mineralization in human dental pulp cells
Kornsuthisopon, C., Manokawinchoke, J., Sonpoung, O., Osathanon, T., & Damrongsri, D. (2021) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2021.105163 · Cited by 6
Orsatti, C. L., Orsatti, F. L., Bezerra, T. G., Quevedo, A. L., & Nahás, E. A. P. (2022) · Gynecological Endocrinology · doi:10.1080/09513590.2022.2105832 · Cited by 6
“Circulating IL-15, however, is necessary to exert such an effect [12,13].”
BackgroundProgression of microstructural deterioration in load-bearing immobilization osteopenia
Koseki, H., Osaki, M., Honda, Y., Sunagawa, S., Imai, C., Shida, T., Matsumura, U., Sakamoto, J., Tomonaga, I., Yokoo, S., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0275439 · Cited by 6
“Besides that, muscle-secreted factors such as interleukin 15 and irisin increase bone mineral content and promote osteoblast differentiation [10, 40, 41].”
BackgroundMyokines: A central point in managing redox homeostasis and quality of life
Rathor, R., & Suryakumar, G. (2024) · BioFactors · doi:10.1002/biof.2054 · Cited by 6
Metadata
- Authors
- Quinn, L. S., Anderson, B. G., Strait-Bodey, L., Stroud, A. M., & Argilés, J. M.
- Affiliations
- VA Puget Sound Health Care System (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2009-01
- Volume
- 296
- Issue
- 1
- Pages
- E191-E202
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC2636988
- OpenAlex
- W2167204431
- Cited by
- 267
- References
- 78
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 10 · 2023: 12 · 2022: 21 · 2021: 18 · 2020: 16 · 2019: 16 · 2018: 24 · 2017: 21 · 2016: 14 · 2015: 21 · 2014: 16 · 2013: 16 · 2012: 21
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG024136, P30AG013280)
- National Institute of Diabetes and Digestive and Kidney Diseases (5-P30-DK-17047, P30DK017047)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- IL-15, myokines, skeletal muscle, adiposity, fat deposition, transgenic mice, bone mineral content, high-fat diet, sex differences, body composition, obesity
- MeSH terms
- Animals, Body Composition, Crosses, Genetic, Dietary Fats, Female, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, RNA, Messenger, Specific Pathogen-Free Organisms, Muscle, Skeletal, Interleukin-15, Reverse Transcriptase Polymerase Chain Reaction, Adiposity, Mice
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