Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states

Beckey Trinh; Signe Johanne Rasmussen; Mathilde Ehnhuus Brøgger-Jensen; Christoph Andreas Engelhard; Anton Lund; Ana Rita Tavanez; Alexandra Vassilieva; Susanne Janum; Ulrik Winning Iepsen; Bente Kiens; Kirsten Møller; Bente Klarlund Pedersen; Gerrit Van Hall; Helga Ellingsgaard

doi:10.1016/j.xcrm.2025.102042

Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states

Beckey Trinh, Signe Johanne Rasmussen, Mathilde Ehnhuus Brøgger-Jensen, Christoph Andreas Engelhard, Anton Lund, Ana Rita Tavanez, Alexandra Vassilieva, Susanne Janum, Ulrik Winning Iepsen, Bente Kiens, Kirsten Møller, Bente Klarlund Pedersen, Gerrit Van Hall, Helga Ellingsgaard^*

^*Corresponding author for this work

1 Citation (Scopus)

Abstract

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).

Original language	English
Article number	102042
Journal	Cell reports. Medicine
Volume	6
Issue number	4
ISSN	2666-3791
DOIs	https://doi.org/10.1016/j.xcrm.2025.102042
Publication status	Published - 15 Apr 2025

Keywords

Adult
Antibodies, Monoclonal, Humanized/pharmacology
Fasting/metabolism
Fatty Acids/metabolism
Humans
Interleukin-6/metabolism
Lipolysis/drug effects
Male
Middle Aged
Muscle, Skeletal/metabolism
Phosphorylation/drug effects
Postprandial Period/physiology
Subcutaneous Fat/metabolism
fatty acids
fasting
interleukin-6
nutrients
homeostasis
tocilizumab
isotopes
lipolysis
humans
obesity

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Trinh, B., Rasmussen, S. J., Brøgger-Jensen, M. E., Engelhard, C. A., Lund, A., Tavanez, A. R., Vassilieva, A., Janum, S., Iepsen, U. W., Kiens, B., Møller, K., Pedersen, B. K., Van Hall, G., & Ellingsgaard, H. (2025). Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states. Cell reports. Medicine, 6(4), Article 102042. https://doi.org/10.1016/j.xcrm.2025.102042

Trinh, B, Rasmussen, SJ, Brøgger-Jensen, ME, Engelhard, CA , Lund, A, Tavanez, AR, Vassilieva, A , Janum, S , Iepsen, UW, Kiens, B, Møller, K , Pedersen, BK , Van Hall, G & Ellingsgaard, H 2025, 'Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states', Cell reports. Medicine, vol. 6, no. 4, 102042. https://doi.org/10.1016/j.xcrm.2025.102042

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title = "Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states",

abstract = "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).",

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T1 - Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states

AU - Trinh, Beckey

AU - Rasmussen, Signe Johanne

AU - Brøgger-Jensen, Mathilde Ehnhuus

AU - Engelhard, Christoph Andreas

AU - Lund, Anton

AU - Tavanez, Ana Rita

AU - Vassilieva, Alexandra

AU - Janum, Susanne

AU - Iepsen, Ulrik Winning

AU - Kiens, Bente

AU - Møller, Kirsten

AU - Pedersen, Bente Klarlund

AU - Van Hall, Gerrit

AU - Ellingsgaard, Helga

PY - 2025/4/15

Y1 - 2025/4/15

N2 - 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).

AB - 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).

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KW - Fatty Acids/metabolism

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KW - Male

KW - Middle Aged

KW - Muscle, Skeletal/metabolism

KW - Phosphorylation/drug effects

KW - Postprandial Period/physiology

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KW - fatty acids

KW - fasting

KW - interleukin-6

KW - nutrients

KW - homeostasis

KW - tocilizumab

KW - isotopes

KW - lipolysis

KW - humans

KW - obesity

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DO - 10.1016/j.xcrm.2025.102042

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C2 - 40147447

SN - 2666-3791

VL - 6

JO - Cell reports. Medicine

JF - Cell reports. Medicine

IS - 4

M1 - 102042

ER -

Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states

Abstract

Keywords

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