Regulation of Adipose Tissue Inflammation by Interleukin 6
Open accessAbstract
Significance Chronic low-grade inflammation is a key driver of metabolic syndrome. This inflammatory response is mediated by immune-cell infiltration and the expression of inflammatory cytokines. IL6 is implicated in this response, but the physiological role of IL6 signaling is unclear. Here, we demonstrate that the source of IL6 influences the nature of the inflammatory response. We report that IL6 secreted by myeloid cells inhibits adipose tissue macrophage (ATM) accumulation by a canonical signaling mechanism, but IL6 secreted by adipocytes or muscle promotes ATM accumulation by a noncanonical mechanism. These observations provide physiological insight into the complexity of IL6-mediated regulation of inflammation.
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FGF21 is upregulated by physical activity and may act downstream of these signals to further enhance thermogenic program.
“Additionally, fibroblast growth factor 21 (FGF21) is also upregulated by physical activity and may act downstream of these signals to further enhance the thermogenic program [53].”
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 [53]
The Materials and Methods section describes treadmill exercise in mice, and the Results discuss IL-6 and energy expenditure. Neither those passages nor searches for FGF21 and thermogenesis address whether physical activity upregulates FGF21 or whether FGF21 enhances a thermogenic program. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe opposite actions of IL-6 depending on cell source appeared to be due to a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical trans-signaling mode (adipocytes and muscle) involving increased expression of ADAM10/17 metalloprotease that enhances trans-signaling via soluble IL6 receptor α.
“The finding of opposite actions of IL-6, depending of the cell source, appeared to be due to a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical trans-signaling mode (adipocytes and muscle) which involved increased expression of the ADAM10/17 metalloprotease that enhances trans-signaling via the soluble IL6 receptor α (215).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [215]
In a mouse model with conditional expression of the Il6 gene, IL6 derived from adipocytes increased macrophage infiltration of adipose tissue, while IL6 derived from myeloid cells and muscle suppressed it.
“Using a mouse model with conditional expression of the Il6 gene, it was found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue.”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [215]
IL-6 may induce either pro- or anti-inflammatory actions depending on cell source.
“A recent murine study suggested that IL-6 may induce either pro- or anti-inflammatory actions depending on cell source (215).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [215]
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- Authors
- Han, M. S., White, A., Perry, R. J., Camporez, J.-P., Hidalgo, J., Shulman, G. I., & Davis, R. J.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Yale University (US)
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520;
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Davis, Roger J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-01-24
- Volume
- 117
- Issue
- 6
- Pages
- 2751-2760
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7022151
- OpenAlex
- W3002801990
- Cited by
- 344
- References
- 37
- Citations by year
- 2026: 37 · 2025: 40 · 2024: 53 · 2023: 59 · 2022: 64 · 2021: 57 · 2020: 31 · 2019: 2
- FWCI
- 37.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion, cc-by-nc-nd)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-nd)
- Funders
- American Heart Association (19CDA34660270)
- Ministerio de Economía y Competitividad (SAF2014-56546-R, RTI2018-101105-B-I00)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK107220, R01 DK112698, R01 DK121545, R01 DK116774, R01 DK114793, P30 DK045735)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, adipose tissue inflammation, low-grade inflammation, metabolic syndrome, adipose tissue macrophages, myeloid cells, adipocytes, skeletal muscle, macrophage accumulation, immune cell infiltration
- MeSH terms
- ADAM10 Protein, ADAM17 Protein, Adipose Tissue, Animals, Female, Humans, Macrophages, Male, Mice, Inbred C57BL, Obesity, Species Specificity, Interleukin-6, Adipocytes, Myeloid Cells, Muscle Cells, Mice
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