Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes
Open accessAbstract
In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the proinflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.
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IL-15 is produced by skeletal muscle in response to exercise, acting by autocrine means.
“IL-15 is produced by SkM in response to exercise [123], acting by autocrine means.”
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Cites
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199 · see citing works
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769 · see citing works
Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844 · see citing works
Type 2 diabetes as an inflammatory disease
Donath, M. Y., & Shoelson, S. E. (2011) · Nature Reviews Immunology · doi:10.1038/nri2925 · Cited by 3,737 · see citing works
The pro- and anti-inflammatory properties of the cytokine interleukin-6
Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.034 · Cited by 3,212 · see citing works
Muscles, exercise and obesity: skeletal muscle as a secretory organ
Pedersen, B. K., & Febbraio, M. A. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.49 · Cited by 2,909 · see citing works
Macrophages, inflammation, and insulin resistance
Olefsky, J. M., & Glass, C. K. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135846 · Cited by 2,733 · see citing works
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294 · see citing works
Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., & Cai, D. (2008) · Cell · doi:10.1016/j.cell.2008.07.043 · Cited by 1,350 · see citing works
De Souza, C. T., Araujo, E. P., Bordin, S., Ashimine, R., Zollner, R. L., Boschero, A. C., Saad, M. J. A., & Velloso, L. A. (2005) · Endocrinology · doi:10.1210/en.2004-1520 · Cited by 1,171 · see citing works
Interleukin 15: biology and relevance to human disease
Fehniger, T. A., & Caligiuri, M. A. (2001) · Blood · doi:10.1182/blood.v97.1.14 · Cited by 976 · see citing works
Rao, R. R., Long, J. Z., White, J. P., Svensson, K. J., Lou, J., Lokurkar, I., Jedrychowski, M. P., Ruas, J. L., Wrann, C. D., Lo, J. C., et al. (2014) · Cell · doi:10.1016/j.cell.2014.03.065 · Cited by 973 · see citing works
Qiu, Y., Nguyen, K. D., Odegaard, J. I., Cui, X., Tian, X., Locksley, R. M., Palmiter, R. D., & Chawla, A. (2014) · Cell · doi:10.1016/j.cell.2014.03.066 · Cited by 869 · see citing works
Mechanisms of obesity-associated insulin resistance: many choices on the menuPreprint
Qatanani, M., & Lazar, M. A. (2007) · Genes & Development · doi:10.1101/gad.1550907 · Cited by 780 · see citing works
Holland, W. L., Bikman, B. T., Wang, L.-P., Yuguang, G., Sargent, K. M., Bulchand, S., Knotts, T. A., Shui, G., Clegg, D. J., Wenk, M. R., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43378 · Cited by 705 · see citing works
Mechanisms of insulin resistance in obesity
Ye, J. (2013) · Frontiers of Medicine · doi:10.1007/s11684-013-0262-6 · Cited by 699 · see citing works
Self-citationThe Origins and Drivers of Insulin Resistance
Johnson, A. M. F., & Olefsky, J. M. (2013) · Cell · doi:10.1016/j.cell.2013.01.041 · Cited by 639 · see citing works
Giri, J. G., Kumaki, S., Ahdieh, M., Friend, D. J., Loomis, A., Shanebeck, K. D., DuBose, R. F., Cosman, D. J., Park, L. S., & Anderson, D. M. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00035.x · Cited by 623 · see citing works
Lee, Y. S., Kim, J.-W., Osborne, O., Oh, D. Y., Sasik, R., Schenk, S., Chen, A., Chung, H., Murphy, A., Watkins, S. M., et al. (2014) · Cell · doi:10.1016/j.cell.2014.05.012 · Cited by 598 · see citing works
Kleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.08.013 · Cited by 483 · see citing works
IL-15/IL-15 receptor biology: A guided tour through an expanding universe
Budagian, V., BULANOVA, E., Paus, R., & Bulfone‐Paus, S. (2006) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2006.05.001 · Cited by 386 · see citing works
Oversecretion of interleukin-15 from skeletal muscle reduces adiposity
Quinn, L. S., Anderson, B. G., Strait-Bodey, L., Stroud, A. M., & Argilés, J. M. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90506.2008 · Cited by 267 · cited 1× · see citing works
“In 2009, it was reported that elevation of plasma IL-15 by overexpression of IL-15 in muscle led to a lean phenotype in transgenic mice [38].”
Association between Interleukin-15 and Obesity: Interleukin-15 as a Potential Regulator of Fat Mass
Nielsen, A. R., Højman, P., Erikstrup, C., Fischer, C. P., Plomgaard, P., Mounier, R., Mortensen, O. H., Broholm, C., Taudorf, S., Krogh‐Madsen, R., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2561 · Cited by 194 · see citing works
Azimi, N., Brown, K., Bamford, R. N., Tagaya, Y., Siebenlist, U., & Waldmann, T. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2452 · Cited by 181 · see citing works
Carbó, N., López-Soriano, J., Costelli, P., Alvarez, B., Busquets, S., Baccino, F. M., Quinn, L. S., López-Soriano, F. J., & Argilés, J. M. (2001) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(00)00188-4 · Cited by 174 · see citing works
Inflammation during obesity is not all bad: evidence from animal and human studies
Ye, J., & McGuinness, O. P. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00266.2012 · Cited by 173 · see citing works
Self-citationTamura, Y., Watanabe, K., Kantani, T., Hayashi, J., Ishida, N., & Kaneki, M. (2011) · Endocrine Journal · doi:10.1507/endocrj.k10e-400 · Cited by 137 · cited 1× · see citing works
“IL-15 expression in muscle myotubes is induced by treadmill running in healthy individuals [23], in which IL-15 may promote endurance and fuel supply as suggested by a study of muscle in mice [24].”
Interleukin-15 (IL-15) Induces NF-κB Activation and IL-8 Production in Human Neutrophils
McDonald, P. P., Russo, M. P., Ferrini, S., & Cassatella, M. A. (1998) · Blood · doi:10.1182/blood.v92.12.4828 · Cited by 131 · see citing works
Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes
Barra, N. G., Reid, S., MacKenzie, R., Werstuck, G., Trigatti, B. L., Richards, C., Holloway, A. C., & Ashkar, A. A. (2010) · Obesity · doi:10.1038/oby.2009.445 · Cited by 116 · see citing works
IL-15 constrains mast cell–dependent antibacterial defenses by suppressing chymase activities
Orinska, Z., Maurer, M., Mirghomizadeh, F., Bulanova, E., Metz, M., Nashkevich, N., Schiemann, F., Schulmistrat, J., Budagian, V., Giron‐Michel, J., et al. (2007) · Nature Medicine · doi:10.1038/nm1615 · Cited by 115 · see citing works
Alvarez, B., Carbó, N., López‐Soriano, J., Drivdahl, R. H., Busquets, S., López-Soriano, F. J., Argilés, J. M. A., & Quinn, L. S. (2002) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(02)00148-4 · Cited by 108 · see citing works
Quinn, L. S., Anderson, B. G., Conner, J. D., & Wolden-Hanson, T. (2013) · Endocrinology · doi:10.1210/en.2012-1773 · Cited by 102 · see citing works
Insulin Resistance in the Defense against Obesity
Saltiel, A. R. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.001 · Cited by 101 · see citing works
Quinn, L. S., & Anderson, B. G. (2011) · Journal of Obesity · doi:10.1155/2011/456347 · Cited by 73 · see citing works
The NF-κB binding site is essential for transcriptional activation of the IL-15 gene
Washizu, J., Nishimura, H., Nakamura, N., Nimura, Y., & Yoshikai, Y. (1998) · Immunogenetics · doi:10.1007/s002510050393 · Cited by 73 · see citing works
Vijayakumar, A., Wu, Y., Sun, H., Li, X., Jeddy, Z., Liu, C., Schwartz, G. J., Yakar, S., & LeRoith, D. (2011) · Diabetes · doi:10.2337/db11-0814 · Cited by 65 · see citing works
NFĸB is an Unexpected Major Mediator of Interleukin-15 Signaling in Cerebral Endothelia
Stone, K. P., Kastin, A. J., & Pan, W. (2011) · Cellular Physiology and Biochemistry · doi:10.1159/000331720 · Cited by 65 · see citing works
Interleukin‐15 treatment improves glucose homeostasis and insulin sensitivity in obese mice
Barra, N. G., Chew, M. V., Holloway, A. C., & Ashkar, A. A. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01495.x · Cited by 59 · see citing works
Effects of interleukin-15 on lipid oxidation
Almendro, V., Busquets, S., Ametller, E., Carbó, N., Figueras, M., Fuster, G., Argilés, J. M. A., & López-Soriano, F. J. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2005.12.006 · Cited by 55 · see citing works
Vallabhapurapu, S., Powolny‐Budnicka, I., Riemann, M., et al. (2008) · European Journal of Immunology · doi:10.1002/eji.200737830 · Cited by 54 · see citing works
Hiromatsu, T., Yajima, T., Matsuguchi, T., Nishimura, H., Wajjwalku, W., Arai, T., Nimura, Y., & Yoshikai, Y. (2003) · The Journal of Infectious Diseases · doi:10.1086/374643 · Cited by 54 · see citing works
Giron‐Michel, J., Caignard, A., Fogli, M., et al. (2003) · Blood · doi:10.1182/blood-2002-09-2760 · Cited by 53 · see citing works
Effects of IL-15 on rat brown adipose tissue: Uncoupling proteins and PPARs
Almendro, V., Fuster, G., Busquets, S., Ametller, E., Figueras, M., Argilés, J. M., & López‐Soriano, F. J. (2008) · Obesity · doi:10.1038/oby.2007.47 · Cited by 49 · see citing works
IL-15 Can Signal via IL-15Rα, JNK, and NF-κB To Drive RANTES Production by Myeloid Cells
Chenoweth, M. J., Mian, M. F., Barra, N. G., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101883 · Cited by 43 · see citing works
Interleukin-15 Treatment Induces Weight Loss Independent of Lymphocytes
Barra, N. G., Chew, M. V., Reid, S., & Ashkar, A. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039553 · Cited by 31 · see citing works
Rat liver lipogenesis is modulated by interleukin-15
López‐Soriano, J., Carbó, N., Almendro, V., Figueras, M., Ribas, V., Busquets, S., López-Soriano, F. J., & Argilés, J. M. A. (2004) · International Journal of Molecular Medicine · doi:10.3892/ijmm.13.6.817 · Cited by 16 · see citing works
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Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives
Das, D. K., Graham, Z. A., & Cardozo, C. P. (2020) · Acta Physiologica · doi:10.1111/apha.13367 · Cited by 129 · see citing works
IL-15 activates the Jak3/STAT3 signaling pathway to mediate glucose uptake in skeletal muscle cells
Krolopp, J. E., Thornton, S. M., & Abbott, M. J. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00626 · Cited by 104 · see citing works
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Nadeau, L., & Aguer, C. (2019) · Applied Physiology Nutrition and Metabolism · doi:10.1139/apnm-2018-0022 · Cited by 83 · see citing works
- Authors
- Ye, J.
- Affiliations
- Pennington Biomedical Research Center (US)
- Corresponding author
- Ye, Jianping
- ORCID
- Ye, Jianping
- Venue
- Frontiers of Medicine
- Published
- 2014-12-15
- Volume
- 9
- Issue
- 2
- Pages
- 139-145
- ISSN
- 1673-7342 (ISSN-L)
- 2095-0217
- 2095-0225
- PMC
- PMC4559335
- OpenAlex
- W2065202890
- Cited by
- 66
- References
- 46
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 7 · 2015: 4
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Frontiers of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-085495, R56DK068036, R01DK085495, R01DK068036, DK068036)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- IL-15, obesity, type 2 diabetes, energy expenditure, insulin sensitivity, inflammatory cytokines, brown adipose tissue, lipogenesis, leptin receptor, NF-κB signaling, JAK/STAT signaling, PI3K/Akt signaling, immune cells, weight gain
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Humans, Inflammation, Obesity, Interleukin-15, Rats
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