Cited by 295Exercise and Physiological ResponsesAdipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and Interactions

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Interleukin 6 as an energy allocator in muscle tissue

Kistner, Timothy M., Pedersen, Bente K., Lieberman, Daniel E.·2022·Nature Metabolism

DOI 10.1038/s42255-022-00538-4

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Abstract

Extensive research has shown that interleukin 6 (IL-6) is a multifunctional molecule that is both proinflammatory and anti-inflammatory, depending on the context. Here, we combine an evolutionary perspective with physiological data to propose that IL-6's context-dependent effects on metabolism reflect its adaptive role for short-term energy allocation. This energy-allocation role is especially salient during physical activity, when skeletal muscle releases large amounts of IL-6. We predict that during bouts of physical activity, myokine IL-6 fulfills the three main characteristics of a short-term energy allocator: it is secreted from muscle in response to an energy deficit, it liberates somatic energy through lipolysis and it enhances muscular energy uptake and transiently downregulates immune function. We then extend this model of energy allocation beyond myokine IL-6 to reinterpret the roles that IL-6 plays in chronic inflammation, as well as during COVID-19-associated hyperinflammation and multiorgan failure.

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Author response: Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis
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Why endometriosis should be classified as a whole-body inflammatory disorder
Rees, A., & Cowley, L. (2026) · doi:10.64628/ab.va95gdh4p
Flexible, multiplexed and wearable biosensor with automatic sweat processing capability for non-invasive interleukin-6 protein monitoring
Yang, W., Jiang, Z., Feng, Y., Wang, H., Zhao, X., Li, F., Huang, C., & Pan, Y. (2026) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2026.139829
Etude des variations de pressions partielles d'oxygène sur les réactions cellulaires chez le sujet sain
Lévêque, C. (2024) · theses.fr (ABES) · doi:10.70675/0d961065ze6e6z464fz8e74zd9c653b2325f
Impact of moderate treadmill training on cytokine levels in rats: influence of age and sex
Santo, R. F. D. E., Zhang, Y., Ro, J. Y., & Silva, J. T. D. (2026) · Frontiers in Aging · doi:10.3389/fragi.2026.1794896
“It plays a crucial role in substrate mobilization and energy metabolism, particularly during periods of high metabolic demand (Kistner, Pedersen and Lieberman, 2022; Pedersen and Febbraio, 2012).”
Key hormones for the control of muscle mass: Myokines
Gu, H., Albrecht, E., Deng, Z., & Maak, S. (2026) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2026.102115
Divergent immune cascades activated by metabolic versus mechanical exercise intensity: revisiting cytokine heterogeneity in “moderate-intensity exercise”
Wang, J.-W., Xun, J.-J., & Jian, L.-N. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1846052
Acute cell‑death and lysosomal stress responses to nicotine and cigarette smoke extract in human mesenchymal stromal cells
Junttila, A., Heikkinen, J., Kylmäoja, E., Hawash, A., Åström, P., Lehenkari, P. P., & Palosaari, S. (2026) · Archives of Toxicology · doi:10.1007/s00204-026-04440-w
“…however, be biologically relevant: IL6 can promote survival under cellular stress by shifting energy metabolism toward a glycolytic, proproliferative phenotype (Kistner et al. 2022 ; Xu et al. 2024 ), potentially at the expense of MSC differentiation (Heikkinen et al. 2024b) and tissue homeostasis.”
Targeting the Skeletal Muscle Microenvironment: A Novel Therapeutic Strategy for Skeletal Muscle Aging
Yu, Y., He, Y., Wang, Y., Wu, C., Zhou, R., Chen, F., & Ma, W. (2026) · The FASEB Journal · doi:10.1096/fj.202601360r
“…whereby myocyte-derived IL-6 primarily exhibits anti-inflammatory and metabolic regulatory functions by stimulating lipolysis and hepatic glucose production [137, 138], while potentially acting as an energy-sensing signal to modulate glucose utilization during muscle glycogen depletion [139].”
Enhanced lactose utilization from milk enriched in Uridine-5’-monophosphate drives hepatic energy storage in young mammals
Gao, L., Liu, L., Yang, X.-D., Long, C.-M., & Wu, X. (2026) · Food Chemistry Molecular Sciences · doi:10.1016/j.fochms.2026.100427
“Moreover, UMP supplementation was associated with higher of the IL-6, IL-6R, sIL-6R, and GP130 protein levels, which may integrate with AMPK signaling to coordinate hepatic glycogen metabolism and lipid utilization (Bertholdt et al., 2018; Kistner et al., 2022; MacDonald et al., 2003).”
Physical activity is associated with improved glycemic control but not with IL-6–glycemic interactions in type 2 diabetes: a cross-sectional study
Ismail, M., Hassan, M. I., Gaffer, A. G. M., Ahmed, A. A., Ali, S. M., Safadi, E., Muthukrishnan, R., Kandakurti, P. K., Elnour, A. A., Elzein, H. O., et al. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1837651
“The hypothesis that exercise functionally reprograms IL-6 signaling remains plausible based on prior experimental literature (4 – 6, 18), but was not statistically supported by the present cross-sectional data and warrants direct testing in longitudinal and mechanistic studies (16).”
Influential
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“Mechanistically, chronic IL-6 activation may divert metabolic resources from muscle maintenance, contributing to weakness and fatigue [40].”
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“…(IL)- 6 was the first cytokine demonstrated to be released into the circulation after exercise and is known to regulate muscle metabolism, energy allocation, cell proliferation, and differentiation (Steensberg et al. 2000; Febbraio et al. 2004; Munoz-Canoves et al. 2013; Kistner et al. 2022).”
Cytokine Profiles as Molecular Markers Associated with Physical Exercise and Insulin Therapy in Patients with Type 2 Diabetes Mellitus
França, D. C. H., Barbosa, A. C., Ribeiro, E. B., Neto, A. M. D. M., França, E. C. H., Borges, M. D., de Marchi, P. G. F., Honório‐França, A. C., & França, E. L. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48070674
“…levels and IL-6 may be important for diabetic patients, especially those who are insulin-dependent, in whom glycemic levels are higher, since IL-6 increases lipolysis and fat oxidation in adipose tissue during exercise and increases insulin sensitivity in patients with type 2 diabetes [55,58,60].”
Functional Analysis of IL-6 Genetic Variants and Their Potential Role in Lipid Homeostasis and Inflammatory Regulation in Colombian Athletes
Ríos, D. C. Z., Gómez, M. Á., Gómez, J. M., Polo, F. A., Sarria, B. O., Rivera, J. A., & Matta, A. J. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48070686
“Interleukin-6 (IL-6) regulates anti-inflammatory cytokines such as Interleukin-1 receptor antagonist (IL-1Ra) and Interleukin-10 (IL-10) and influences carbohydrate and lipid metabolism [7].”
Associations Exist Between Inflammatory and Bone Biomarkers in Young Female Adults Following Acute High-Impact Exercise
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Postpartum blood-milk barrier integrity in Holstein dairy cows with contrasting metabolic status
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Myokines, the Growing Basis for “Exercise Is Medicine”
Heitkamp, H. (2026) · Health · doi:10.4236/health.2026.188047
Synergistic effects of synbiotic, protein supplementation, and resistance training on inflammation, oxidative stress, and muscle strength in older adults with type 2 diabetes mellitus: a RCT triple-blinded study
Bastos, M. F., Longo, P. L., Furtado, G. E., dos Santos, J. R., Rodrigues, A. T., Carvalho, J. V. O., Machado‐Lima, A., Brech, G. C., Bachi, A. L. L., Barros, M. P., et al. (2026) · European Journal of Nutrition · doi:10.1007/s00394-026-04076-7 · Cited by 1
Antientzündliche Ernährung
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“Das Beispiel IL-6 zeigt zudem, dass die biologische Wirkung der Zytokine je nach Herkunftsgewebe variabel ist und sowohl eine pro-als auch eine antiinflammatorische Reaktion anzeigen kann [40, 41].”
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Haq, A. T. A., Yang, P.-P., Shen, P.-C., Tseng, H., Chen, L.-M., Chen, M. A., Yuh, C.-H., & Hsu, H.-L. (2026) · Research Square · doi:10.21203/rs.3.rs-10952514/v1
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Intrinsic IL-6 expression reduces rhIL-6-induced JAK/STAT activation and promotes glucose and oleic acid oxidation in cultured human myoblasts
Srpčič, A., Miš, K., Gantar, B. Ž. B., Dolinar, K., Mjaaseth, U. N., Rustan, A. C., Kase, E. T., Lakota, K., Pirkmajer, K. P., & Pirkmajer, S. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00264.2026
Immunometabolic regulation by skeletal muscles in infections and sepsis
Makarova, S., Arkhipova, A., & Nosenko, M. A. (2026) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2026.100628
Bone biomarker and inflammatory cytokine responses to short-term low energy availability with and without preserved protein intake: a randomized, controlled, multi-period, cross-over trial
Dolan, E., Pinto, R. S., Reina, B. A., Esteves, G. P., Miranda, V. C. A., Roschel, H., Gualano, B., Sale, C., & Swinton, P. A. (2026) · European Journal of Applied Physiology · doi:10.1007/s00421-026-06461-w
Systemic proteomic dynamics of acute exercise reveal genetic links to health and disease
Kurgan, N., Larsen, J. K., Jespersen, N. Z., Díez-Obrero, V., Svenstrup, V., Moreno‐Justicia, R., Heywood, S. E., Lindqvist, C. B., Ottander, L., Samodova, D., et al. (2026) · Nature Metabolism · doi:10.1038/s42255-026-01621-w
“The best-characterized exercise-responsive protein so far is the myokine IL-6, a cytokine released during acute exercise 10 , shown to regulate energy allocation in muscle 11 and mediate long-term adaptations to exercise training 12 .”
Disruption of the Muscle–Brain Axis in Ageing: Role of Myokines in Sarcopenia and Neurodegeneration
Molina, V. A. M., Salinas, C. N. L., Vásquez, C. A., Matos, A., & Riofrío, D. A. (2026) · Cells · doi:10.3390/cells15201910
“Its release from skeletal muscle during physical activity should be distinguished from its involvement in chronic inflammation [11].”
Evaluation of the Protective and Antioxidant Effects of Apilarnil Against Acute Exercise Induced Skeletal Muscle Damage in Rats
BAŞOL, C., Kekeçoğlu, M., & Coşkun, S. K. (2026) · Food Technology and Biotechnology · doi:10.17113/ftb.64.04.26.9325
“Previous studies have reported conflicting effects of whey protein on inflammatory cytokines, with findings indicating reductions [ 48 ], no change [ 49 ] or increases [ 50 ] in inflammatory marker concentrations.”

Authors: Kistner, T. M., Pedersen, B. K., & Lieberman, D. E.
Affiliations: Harvard University (US)
University of Copenhagen (DK)
Corresponding author: Kistner, Timothy M.
Pedersen, Bente K.
Lieberman, Daniel E.
ORCID: Kistner, Timothy M.
Pedersen, Bente K.
Lieberman, Daniel E.
Venue: Nature Metabolism
Publisher: Springer Science and Business Media LLC
Published: 2022-02-24
Volume: 4
Issue: 2
Pages: 170-179
ISSN: 2522-5812 (ISSN-L)
DOI: 10.1038/s42255-022-00538-4
OpenAlex: W4213414654
Cited by: 295
References: 149
Citations by year: 2026: 54 · 2025: 87 · 2024: 68 · 2023: 56 · 2022: 30
FWCI: 7.14
Type: journal article
Language: en
Open access: closed
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Metabolism (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords: interleukin-6, myokines, energy allocation, skeletal muscle, physical activity, lipolysis, energy metabolism, chronic inflammation, multiple organ failure, evolutionary perspective
MeSH terms: COVID-19, SARS-CoV-2, Humans, Exercise, Interleukin-6, Muscle, Skeletal

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Interleukin 6 as an energy allocator in muscle tissue

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