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Interleukin-6 Signaling in Liver-Parenchymal Cells Suppresses Hepatic Inflammation and Improves Systemic Insulin Action
Open accessAbstract
The contribution of interleukin (IL)-6 signaling in obesity-induced inflammation remains controversial. To specifically define the role of hepatic IL-6 signaling in insulin action and resistance, we have generated mice with hepatocyte-specific IL-6 receptor (IL-6R) alpha deficiency (IL-6Ralpha(L-KO) mice). These animals showed no alterations in body weight and fat content but exhibited a reduction in insulin sensitivity and glucose tolerance. Impaired glucose metabolism originated from attenuated insulin-stimulated glucose transport in skeletal muscle and fat. Surprisingly, hepatic IL-6Ralpha-disruption caused an exaggerated inflammatory response during euglycemic hyperinsulinemic clamp analysis, as revealed by increased expression of IL-6, TNF-alpha, and IL-10, as well as enhanced activation of inflammatory signaling such as phosphorylation of IkappaBalpha. Neutralization of TNF-alpha or ablation of Kupffer cells restored glucose tolerance in IL-6Ralpha(L-KO) mice. Thus, our results reveal an unexpected role for hepatic IL-6 signaling to limit hepatic inflammation and to protect from local and systemic insulin resistance.
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“Here, regardless of stress-priming, animals lacking hepatic IL6 signaling were significantly more sensitive to endotoxemia, suggesting that the hepatic acute phase response was a required adaptation to endotoxemia (Figure S5B), consistent with previous reports (Castell et al., 1989; Wunderlich et al., 2010).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Wunderlich et al., 2010
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“Mice with hepatocyte-specific deletion of IL-6Rα still exhibited reduced insulin sensitivity and glucose tolerance, suggesting a protective role of hepatic IL-6 signaling (Wunderlich et al., 2010”
From Targeting Interleukin-6 Signaling in Clinic (2019) · cites this paper as Wunderlich et al., 2010
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Type 2 diabetes as an inflammatory disease
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“Analysis of hepatocyte-specific deletion of the IL-6 receptor in mice has added to the controversy, as these mice seem to be protected from both local and systemic insulin resistanc”
BackgroundThe pro- and anti-inflammatory properties of the cytokine interleukin-6
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“Most studies in vitro and in mice suggest that adipose-derived IL-6 promotes hepatic insulin resistance and glucose intolerance (259, 262, 263), while some indicate that in certain contexts IL-6 signaling in WAT and liver may be protective against metabolic disease (264, 265).”
Background
Metadata
- Authors
- Wunderlich, F. T., Ströhle, P., Könner, A. C., Gruber, S., Tovar, S., Brönneke, H. S., Juntti-Berggren, L., Li, L.-S., van Rooijen, N., Libert, C., Berggren, P.-O., & Brüning, J. C.
- Affiliations
- University of Cologne (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Karolinska Institutet (SE)
- Vlaams Instituut voor Biotechnologie (BE)
- Corresponding author
- Brüning, Jens C.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 12
- Issue
- 3
- Pages
- 237-249
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2090699565
- Cited by
- 229
- References
- 48
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 12 · 2022: 12 · 2021: 13 · 2020: 15 · 2019: 17 · 2018: 22 · 2017: 21 · 2016: 12 · 2015: 15 · 2014: 14 · 2013: 12 · 2012: 18
- FWCI
- 10.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1086 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (1492-7-1, SFB 635, SFB 832)
- Novartis Foundation
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- IL-6 signaling, IL-6 receptor alpha, hepatocytes, liver inflammation, insulin resistance, insulin sensitivity, glucose tolerance, TNF-α, Kupffer cells, obesity-associated inflammation, insulin-stimulated glucose transport, NF-κB signaling, skeletal muscle, adipose tissue
- MeSH terms
- Animals, Energy Metabolism, Glucose, Glycogen, Homeostasis, Humans, Inflammation, Insulin, Insulin Resistance, Kupffer Cells, Liver, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Interleukin-10, Mice, Knockout, Receptors, Interleukin-6, Adiposity, Mice
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