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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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“Furthermore, the differential gene expression was computed between these groups and represented as a dot plot as depicted in Figure 5C.”
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“However, the detrimental effects of the above described hepatic IL-6 signalling on insulin resistance have been challenged using mice that lack the IL-6 receptor α specifically in the liver (Wunderlich et al. 2010).”
BackgroundFrisdal, É., Lesnik, P., Olivier, M., Robillard, P., Chapman, M. J., Huby, T., Guérin, M., & Goff, W. L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.264325 · Cited by 118
Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia
Tsoli, M., Swarbrick, M. M., & Robertson, G. R. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.10.039 · Cited by 113
Ling, J., Chaba, T., Zhu, L.-F., Jacobs, R. L., & Vance, D. E. (2011) · Hepatology · doi:10.1002/hep.24782 · Cited by 104
“Of note, IL-6 inhibits insulin-stimulated glycogen synthesis in rat hepatocytes.(38) Therefore, the inflammatory response induced by low hepatic PC/PE in HF-fed Pemt / mice may also contribute to mortality after PH by impairing glycogen storage.”
BackgroundCimini, F. A., Barchetta, I., Carotti, S., Bertoccini, L., Baroni, M. G., Vespasiani-Gentilucci, U., Cavallo, M.-G., & Morini, S. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i19.3407 · Cited by 101
The role of interleukin-6 in glucose homeostasis and lipid metabolism
Lehrskov, L. L., & Christensen, R. H. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00747-2 · Cited by 114
Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance
Wueest, S., Item, F., Lucchini, F. C., Challa, T. D., Müller, W., Blüher, M., & Konrad, D. (2015) · Diabetes · doi:10.2337/db15-0941 · Cited by 103
“Although we are aware that knockout of gp130 in adipocytes affects the signaling pathway of all members of the IL-6 cytokines, the mouse model still seems adequate to investigate our hypothesis because the mIL-6R is not expressed in adipocytes (7), precluding cell-specific depletion of IL-6 signaling in adipocytes sim…”
BackgroundResultDiet-induced gut dysbiosis and inflammation: Key drivers of obesity-driven NASH
Kang, G. G., Trevaskis, N. L., Murphy, A. J., & Febbraio, M. A. (2023) · iScience · doi:10.1016/j.isci.2022.105905 · Cited by 94
Yekollu, S. K., Thomas, R., & O’Sullivan, B. (2011) · Diabetes · doi:10.2337/db11-0275 · Cited by 94
Liver innate immune cells and insulin resistance: the multiple facets of Kupffer cells
Jager, J., Aparicio‐Vergara, M., & Aouadi, M. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12483 · Cited by 90
IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice
Wu, R., Liu, X., Yin, J., Wu, H., Cai, X., Wang, N., Qian, Y., & Wang, F. (2018) · Metabolism · doi:10.1016/j.metabol.2018.01.002 · Cited by 90
Xu, E., Pereira, M. M. A., Karakasilioti, I., Theurich, S., Al-Maarri, M., Rappl, G., Waisman, A., Wunderlich, F. T., & Brüning, J. C. (2017) · Nature Communications · doi:10.1038/ncomms14803 · Cited by 95
“To generate mice with T cell-specific IL-6R a deficiency (IL-6R a T-KO ), we crossed mice hemizygous for a transgene in which transcription of the Cre recombinase is controlled by the Cd4 promoter (CD4-Cre) 26 with mice homozygous for LoxP -flanked Il6ra alleles (IL-6R a f/f ) 27 .”
Silva, A. K. S., & Peixoto, C. A. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2838-4 · Cited by 89
“The dysregulated release of cytokines following liver damage may result in the excessive death of hepatocytes, which is a key event in several acute and chronic liver diseases [17].”
BackgroundInfluentialSignaling pathways and intervention for therapy of type 2 diabetes mellitus
Cao, R. Y., Tian, H., Zhang, Y., Liu, G., Xu, H., Rao, G., Tian, Y., & Fu, X. (2023) · MedComm · doi:10.1002/mco2.283 · Cited by 98
Interleukin-6 gene transfer reverses body weight gain and fatty liver in obese mice
Ma, Y., Gao, M., Sun, H. Y., & Liu, D. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.01.017 · Cited by 92
Atar, N., & Yola, M. L. (2021) · Analytica Chimica Acta · doi:10.1016/j.aca.2021.338202 · Cited by 87
A subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis
Reilly, S. M., Ahmadian, M., Zamarron, B. F., Chang, L. C., Uhm, M., Poirier, B., Peng, X., Krause, D., Korytnaya, E., Neidert, A., et al. (2015) · Nature Communications · doi:10.1038/ncomms7047 · Cited by 89
“IL-6 signalling has previously been shown to have anti-inflammatory effects in liver as well as inflammatory cells 24,25 .”
Buechler, C., Haberl, E. M., Rein‐Fischboeck, L., & Aslanidis, C. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18071392 · Cited by 87
“On the other hand, IL-6 signaling specifically in hepatocytes protects the animals from hepatic inflammation and insulin resistance [169] (Figure 2).”
BackgroundLipid Sensing and Insulin Resistance in the Brain
Yue, J. T. Y., & Lam, T. K. T. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.013 · Cited by 83
Efeito do exercício no sistema imune: resposta, adaptação e sinalização celular
Terra, R., Da-Silva, S. A. G., Salerno, V. P., & Dutra, P. M. L. (2012) · Revista Brasileira de Medicina do Esporte · doi:10.1590/s1517-86922012000300015 · Cited by 84
Adipokines in obesity and metabolic-related-diseases
Pestel, J., Blangero, F., Watson, J., Pirola, L., & Eljaafari, A. (2023) · Biochimie · doi:10.1016/j.biochi.2023.04.008 · Cited by 83
Becker, M., Joseph, S. S., García-Carrizo, F., Tom, R. Z., Opaleva, D., Serr, I., Tschöp, M., Schulz, T. J., Hofmann, S., & Daniel, C. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.08.010 · Cited by 71
Fucoidan from sea cucumber may improve hepatic inflammatory response and insulin resistance in mice
Wang, J., Hu, S., Jiang, W., Song, W., Cai, L., & Wang, J. (2015) · International Immunopharmacology · doi:10.1016/j.intimp.2015.12.009 · Cited by 72
Anti-Inflammatory Effect of Resveratrol in Old Mice Liver
Tung, B. T., Rodríguez-Bies, E., Talero, E., Gamero-Estévez, E., Motilva, V., Navas, P., & López-Lluch, G. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2015.02.004 · Cited by 71
“Among these factors, IL-6 is a cytokine with pleiotropic effects and its increase is associated with chronic inflammations, autoimmune diseases, and hematopoietic disorders (Wunderlich et al., 2010).”
BackgroundDeficiency in Interferon-γ Results in Reduced Body Weight and Better Glucose Tolerance in Mice
Wong, N., Fam, B. C., Cempako, G. R., Steinberg, G. R., Walder, K. R., Kay, T. W. H., Proietto, J., & Andrikopoulos, S. (2011) · Endocrinology · doi:10.1210/en.2011-0288 · Cited by 70
Kim, Y. D., Kim, Y. H., Cho, Y. M., Kim, D. K., Ahn, S.-W., Lee, J., Chanda, D., Shong, M., Lee, C., & Choi, H.-S. (2012) · Diabetologia · doi:10.1007/s00125-012-2494-4 · Cited by 70
The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism
von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., König, J., Fromm, M. F., Horn, P., Chatzigeorgiou, A., et al. (2017) · Hepatology · doi:10.1002/hep.29089 · Cited by 70
“In these animals, a compensatory increase in many other cytokines has been reported.((21)) In contrast, low-dose application of murine IL-6 in mice leads to hepatic steatosis.”
BackgroundMethodInfluentialThe biology behind interleukin-6 targeted interventions
Liu, X., Jones, G. W., Choy, E., & Jones, S. A. (2016) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000255 · Cited by 52
Exerkines and cardiometabolic benefits of exercise: from bench to clinic
Jin, L., Díaz-Cañestro, C., Wang, Y., Tse, M. A., & Xu, A. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00027-z · Cited by 76
“For example, mice with hepatocyte-speci fi c IL-6RA de fi ciency displayed systemic insulin resistance and notable hepatic in fl am-mation even under a normal diet (Wunderlich et al, 2010).”
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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