Skeletal muscle IL-6 regulates muscle substrate utilization and adipose tissue metabolism during recovery from an acute bout of exercise
Open accessAbstract
An acute bout of exercise imposes a major challenge on whole-body metabolism and metabolic adjustments are needed in multiple tissues during recovery to reestablish metabolic homeostasis. It is currently unresolved how this regulation is orchestrated between tissues. This study was undertaken to clarify the role of skeletal muscle derived interleukin 6 (IL-6) in the coordination of the metabolic responses during recovery from acute exercise. Skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate Control mice were rested or ran on a treadmill for 2h. Plasma, skeletal muscle, liver and adipose tissue were obtained after 6 and 10h of recovery. Non-exercised IL-6 MKO mice had higher plasma lactate and lower plasma non-esterified fatty acids than Controls. The activity of pyruvate dehydrogenase in the active form was, in skeletal muscle, higher in IL-6 MKO mice than Controls in non-exercised mice and 6h after exercise. IL-6 MKO mice had lower glucose transporter 4 protein content in inguinal adipose tissue (WAT) than Control in non-exercised mice and 10h after treadmill running. Epididymal WAT hormone sensitive lipase phosphorylation and inguinal WAT mitogen activated kinase P38 phosphorylation were higher in IL-6 MKO than Control mice 6h after exercise. These findings indicate that skeletal muscle IL-6 may play an important role in the regulation of substrate utilization in skeletal muscle, basal and exercise-induced adaptations in adipose tissue glucose uptake and lipolysis during recovery from exercise. Together this indicates that skeletal muscle IL-6 contributes to reestablishing metabolic homeostasis during recovery from exercise by regulating WAT and skeletal muscle metabolism.
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A separate human study found that IL-6 infusion stimulates lipolysis and lipid oxidation.
“However, another study of IL-6 infusion into humans found that IL-6 stimulates lipolysis and lipid oxidation54,121.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [54]
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“Although speculative, enhanced PDH flux in the BLOCK group, by favoring mitochondrial oxidation over rapid glycolytic ATP generation, may also have contributed to reduced lactate production and altered acute energy turnover [32,33].”
Liang, L.-B., Zhao, Z.-H., Li, W.-X., Wang, S., Shen, Q., Wu, C.-Q., & Li, K.-P. (2026) · Cardiovascular Diabetology · doi:10.1186/s12933-026-03236-7 · Cited by 1 · see citing works
“For example, the role of IL-6 in lipolysis and glucose homeostasis remains disputed [24–27].”
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“On the other hand, there is evidence of the positive effects of muscle-derived IL-6 on energy homeostasis through stimulation of glucose uptake and lipolysis in adipose tissue (Knudsen et al. 2017).”
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Prescribing Exercise as a Lifestyle Intervention
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- Authors
- Knudsen, J. G., Gudiksen, A., Bertholdt, L., Overby, P., Villesen, I., Schwartz, C. L., & Pilegaard, H.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Knudsen, Jakob G.
- Pilegaard, Henriette
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-12-18
- Volume
- 12
- Issue
- 12
- Pages
- e0189301
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5734691
- OpenAlex
- W2776293860
- Cited by
- 42
- References
- 42
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 4 · 2018: 2 · 2016: 1
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Lundbeckfonden
- Statens Naturvidenskabelige Forskningsrad
- Danish diabetes association
- Augustinus Fonden
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- post-exercise recovery, adipose tissue metabolism, glucose uptake, lipolysis, pyruvate dehydrogenase, glucose transporter 4, hormone-sensitive lipase, p38 MAPK, metabolic homeostasis, IL-6 knockout mice
- MeSH terms
- Adipose Tissue, Animals, Blood Glucose, Glucose, Glycogen, Homeostasis, Liver, Male, Mice, Inbred C57BL, Phosphorylation, Physical Conditioning, Animal, Signal Transduction, Interleukin-6, Mice, Knockout, Muscle, Skeletal, Mice
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