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Interleukin 6 as an energy allocator in muscle tissue
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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“While IL-6 released during exercise promotes insulin-independent glucose uptake by inducing the translocation of GLUT4 transporters in adipose tissue via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [49]
In the citing paper
“IL-6 also promotes hepatic gluconeogenesis by activating key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) [49,50].”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [49]
In the citing paper
“Circulating IL-6 concentrations increase dramatically in response to exercise and are intricately tied to exercise intensity, meaning that IL-6 is released from the skeletal muscle to restore muscle function following exercise [110].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [110]
In the citing paper
“In summary, our results extend the concept of exercise-induced, muscle-derived IL-6 as an energy sensor and energy allocator [ 7 , 8 ], involved in intensity-dependent fuel selection [ 34 ].”
From IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men (2026) · cites this paper as [8]
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“19 In healthy individuals, IL-6 released through skeletal muscle during exercises induces lipolysis and beta-oxidation.”
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“In addition to its role in tissue repair, IL-6 acts as a myokine involved in energy metabolism and muscle remodeling during exercise [21–23].”
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“Its effects on skeletal muscle are complex (Scheller et al., 2011; Kistner et al., 2022), yet most germane to our work are studies showing that IL-6 promotes both muscle catabolism (Bakker and Jaspers, 2015) and insulin resistance (Pedersen and Edward, 2009), with chronic IL-6 administration inducing skeletal muscle a…”
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“Interestingly, IL6 has a role as an energy allocator (reviewed in (Kistner et al., 2022)), exhibiting both anabolic and catabolic effects.”
BackgroundElevated Plasma IL-6 Coincides with Activation of STAT3 in PBMC After Acute Resistance Exercise
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Il-6 signaling exacerbates hallmarks of chronic tendon disease by stimulating reparative fibroblasts
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“21,50 The peak concentration of IL-6 depends on the intensity of the exercise.”
Acute exercise modulates Trim63 and Bmal1 in the skeletal muscle of IL-10 knockout mice
da Mata, G. E., Brícola, R. S., Ribeiro, D. N., Simabuco, F. M., Pauli, J. R., de Freitas, E. C., Ropelle, E. R., da Silva, A. S. R., & Pinto, A. P. (2023) · Cytokine · doi:10.1016/j.cyto.2023.156484 · Cited by 4
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“Lastly, SM produces various interleukins that control key processes in hemato - poietic cells, and muscle depletion may lead to higher risks of hematologic toxicity [37 ].”
Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease
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Global multi-omics analysis of exerkines in progressive treadmill-exercised rodentsPreprint
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“During the recovery phase, this rise in IL-6 helps to calm down the inflammation and reduce oxidative stress post exercise [44,45].”
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“…classical signaling pathway, IL-6 binds to the membrane-bound IL-6R that is present on a select range of cell types, namely, hepatocytes and certain leukocytes, resulting in the trimerization with two units of the ubiquitously expressed signal-transducing coreceptor glycoprotein 130 (gp130) ( 12 ).”
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“IL-6 coordinates short-term energy allocationviaIL-6signaling 62 ,andtriggersthereleaseoffreefattyacidsfrom lipolysis,glycogenolysisintheliverthatpromotesthereleaseofglucose,and inducesperipheralglucosemetabolismviaactivationofAMPK 63,64 .”
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“Highly cited work from this institution frequently addressed exercise-related immunometabolic mechanisms, including myokine-mediated regulation of in fl ammation (76, 77).”
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“It is understood that the local generation of proinflammatory cytokines at the site of tissue injury or infection will activate host non-specific immunity [6].”
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“IL-6 is one of the most essential myokines, and evidence suggests that the function of muscle-derived IL-6 is not pro-inflammatory but related to glucose and lipid metabolism (Kistner et al., 2022).”
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IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men
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“These results are conducted by Leal et al. (2018) said endurance exercise can induce myocytes that can modulate adipose tissue to produce increased gene expression and secretion of IL-6, and there is an increase in IL-10, IL1-ra, and TNF-a, which is characterized as an anti-inflammatory effect.”
BackgroundCoordination of Glucose and Glutamine Metabolism in Tendon Is Lost in Aging
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“IL ‐ 6 regulates glucose metabolism with increased levels of IL ‐ 6 being associated with increased ability to metabolize glucose [66].”
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Roles of plasminogen activator inhibitor-1 in aging-related muscle and bone loss in mice
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Peptide hormones and bile acids shaping immune tolerance of the liver: implications and applications
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Metadata
- 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.
- Venue
- Nature Metabolism
- Published
- 2022-02-24
- Volume
- 4
- Issue
- 2
- Pages
- 170-179
- ISSN
- 2522-5812 (ISSN-L)
- 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
- 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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