Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial
Open accessAbstract
Visceral adipose tissue is harmful to metabolic health. Exercise training reduces visceral adipose tissue mass, but the underlying mechanisms are not known. Interleukin-6 (IL-6) stimulates lipolysis and is released from skeletal muscle during exercise. We hypothesized that exercise-induced reductions in visceral adipose tissue mass are mediated by IL-6. In this randomized placebo-controlled trial, we assigned abdominally obese adults to tocilizumab (IL-6 receptor antibody) or placebo during a 12-week intervention with either bicycle exercise or no exercise. While exercise reduced visceral adipose tissue mass, this effect of exercise was abolished in the presence of IL-6 blockade. Changes in body weight and total adipose tissue mass showed similar tendencies, whereas lean body mass did not differ between groups. Also, IL-6 blockade increased cholesterol levels, an effect not reversed by exercise. Thus, IL-6 is required for exercise to reduce visceral adipose tissue mass and emphasizes a potentially important metabolic consequence of IL-6 blockade.
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Obese adults receiving tocilizumab and subjected to 12 weeks of endurance exercise showed a blunted exercise-induced loss of visceral fat mass compared with controls, as measured by DEXA.
“Obese adults receiving tocilizumab, subjected to 12 weeks of endurance exercise, showed a blunted exercise-induced loss of visceral fat mass compared with controls, as measured by DEXA [78].”
Blocking IL-6 signaling with tocilizumab during exercise blunts this metabolic effect and prevents the reduction in fat, underscoring key role of IL-6 in exercise-induced fat mobilization.
“Conversely, blocking IL-6 signaling with tocilizumab during exercise blunts this metabolic effect and prevents the reduction in fat, underscoring the key role of IL-6 in exercise-induced fat mobilization [46].”
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 [46]
Intravenous administration of IL-6 at higher concentrations (>100 pg/mL, comparable to strenuous exercise) stimulates lipolysis.
“another study has shown that the intravenous administration of IL-6 at higher concentrations (>100 pg/mL, comparable to those used during strenuous exercise) stimulates lipolysis.”
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 [46]
IL-6 mediates the exercise-associated anti-inflammatory effects both acutely with each bout of exercise and as a consequence of training adaptation, including reduction in abdominal adiposity.
“The myokine IL-6 mediates the exercise-associated anti-inflammatory effects both acutely with each bout of exercise and as a consequence of training adaptation, including reduction in abdominal adiposity.”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [136]
Exercise training leads to a decrease in visceral and cardiac fat mass and hence a decrease in circulating inflammatory molecules via a mechanism that involves exercise-induced increase in IL-6.
“Exercise training will lead to a decrease in visceral and cardiac fat mass (136, 138, 221) and hence a decrease in circulating inflammatory molecules via a mechanism that involves exercise-induced increase in IL-6 (136), as described above.”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [136]
Acute exercise in humans releases molecules such as GDF15 and IL-6 that affect lipolysis, in addition to adrenaline.
“acute exercise in humans also releases additional molecules79, such as growth and differentiation factor 15 (GDF15)80 and IL-6 (REF.81), which also affect lipolysis”
From Exerkines in health, resilience and disease (2022) · cites this paper as [81]
IL-6R blockade does not influence perceived exertion during moderate-intensity exercise.
“Notably, this effect appears specific to high-intensity exercise, as IL-6R blockade does not influence perceived exertion during moderate-intensity exercise [ 34 , 44 ].”
From IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men (2026) · cites this paper as [44]
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- Authors
- Wedell-Neergaard, A.-S., Lang Lehrskov, L., Christensen, R. H., Legaard, G. E., Dorph, E., Larsen, M. K., Launbo, N., Fagerlind, S. R., Seide, S. K., Nymand, S., Ball, M., Vinum, N., Dahl, C. N., Henneberg, M., Ried-Larsen, M., Nybing, J. D., Christensen, R., Rosenmeier, J. B., Karstoft, K., Pedersen, B. K., Ellingsgaard, H., & Krogh-Madsen, R.
- Affiliations
- University of Copenhagen (DK)
- Bispebjerg Hospital (DK)
- Corresponding author
- Ellingsgaard, Helga
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 29
- Issue
- 4
- Pages
- 844-855.e3
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2906928401
- Cited by
- 403
- References
- 54
- Citations by year
- 2026: 38 · 2025: 54 · 2024: 56 · 2023: 56 · 2022: 64 · 2021: 59 · 2020: 42 · 2019: 33
- FWCI
- 26.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Danish Diabetes Academy
- TrygFonden
- Novo Nordisk Fonden
- Oak Foundation (OCAY-13-309)
- Hjerteforeningen (16-R107-A6704-22970)
- Strategiske Forskningsråd (09-067009, 09-075724)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Keywords
- visceral adipose tissue, interleukin-6, exercise training, tocilizumab, IL-6 receptor inhibition, abdominal obesity, lipolysis, skeletal muscle, cholesterol, body weight, lean body mass, adipose tissue mass
- MeSH terms
- Adult, Double-Blind Method, Female, Humans, Male, Middle Aged, Organ Size, Signal Transduction, Exercise, Interleukin-6, Intra-Abdominal Fat
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