Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states
Interleukin-6 (IL-6) knockout mice and humans treated with IL-6 receptor blockade gain adipose tissue mass. This study investigates whether basal IL-6 activity (resting IL-6 levels) influences fat storage during fasting and postprandial states. Using stable-isotope tracer techniques and IL-6 receptor blockade with tocilizumab, we examine fat kinetics in humans. Blocking basal IL-6 activity reduces fasting whole-body lipolysis, decreases hormone-sensitive lipase (HSL) phosphorylation and fatty acid release in adipose tissue, and impairs postprandial fatty acid uptake in the leg. These results suggest diminished fatty acid uptake and oxidation in skeletal muscle, along with enhanced fatty acid entrapment in adipose tissue, which may account for the increased adiposity in the absence of IL-6 activity. Additionally, IL-6 blockade increases the escape of meal-derived fatty acids into the bloodstream. Whether this affects fatty acid storage and lipotoxicity in other tissues warrants further investigation. This study was registered at ClinicalTrials.gov (NCT04687540).
Authors
- Ulrik Winning Iepsen (ORCID: https://orcid.org/0000-0002-8140-2583)
- Anton Lund (ORCID: https://orcid.org/0000-0002-0464-8328)
- Gerrit van Hall (ORCID: https://orcid.org/0000-0002-2519-8127)
- Christoph Andreas Engelhard (ORCID: https://orcid.org/0000-0002-2389-839X)
- Alexandra Vassilieva (ORCID: https://orcid.org/0000-0002-9476-5850)
- Bente Kiens (ORCID: https://orcid.org/0000-0001-5705-5625)
- Beckey Trinh (ORCID: https://orcid.org/0000-0003-2784-7079)
- Kirsten Møller (ORCID: https://orcid.org/0000-0003-3058-1072)
- Bente Klarlund Pedersen (ORCID: https://orcid.org/0000-0001-6508-6288)
- Helga Ellingsgaard (ORCID: https://orcid.org/0000-0002-9105-5247)
- Sten Rasmussen (ORCID: https://orcid.org/0000-0002-8664-352X)
- Susanne Janum
- Ana Rita Tavanez
- Mathilde Ehnhuus Brøgger-Jensen
Institutions
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102042
- Citations
- 8
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 9.31
Funders
- National Science Foundation
- Universität Basel
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Novo Nordisk
- TrygFonden
- Novo Nordisk Fonden