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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IL-6 released during exercise promotes insulin-independent glucose uptake by inducing translocation of GLUT4 transporters in adipose tissue via PI3K/Akt signaling.
“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]
IL-6 promotes hepatic gluconeogenesis by activating key gluconeogenic enzymes including PEPCK and G-6-Pase.
“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]
Circulating IL-6 concentrations increase dramatically in response to exercise and are intricately tied to exercise intensity, meaning IL-6 is released from skeletal muscle to restore muscle function following exercise.
“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]
Our results extend the concept of exercise-induced, muscle-derived IL-6 as an energy sensor and energy allocator involved in intensity-dependent fuel selection.
“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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Exercise Metabolism and Adaptation in Skeletal Muscle
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- 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 › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Oncology › 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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