The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance
Open accessAbstract
Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 (-/-)) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance.Methods Male, 8-week-old Il6 (-/-) and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly.Results Il6 (-/-) mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 (-/-) and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 (-/-) mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 (-/-) relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins.Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The anti-inflammatory properties of IL-6 are illustrated by IL-6−/− mice, which exhibit hepatosteatosis, insulin resistance, and liver inflammation (44).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [44]
In the citing paper
“On the other hand, in these same contexts, others have shown that IL6 induces insulin sensitivity (Carey et al., 2006; Findeisen et al., 2019; Matthews et al., 2010; Mauer et al., 2014; Steensberg et al., 2003; Timper et al., 2017), while IL6 has been shown to be insulin sensitizing in exercise (Benrick et al., 2012).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Matthews et al., 2010
Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199
Ghrelin induces adiposity in rodents
Tschöp, M., Smiley, D. L., & Heiman, M. L. (2000) · Nature · doi:10.1038/35038090 · Cited by 3,949
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359
Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6
Pedersen, B. K., & Febbraio, M. A. (2008) · Physiological Reviews · doi:10.1152/physrev.90100.2007 · Cited by 2,388
Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., & Shoelson, S. E. (2005) · Nature Medicine · doi:10.1038/nm1166 · Cited by 2,245
Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R., & Shulman, G. I. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa031314 · Cited by 2,193
Mitochondrial dysfunction in the elderly: possible role in insulin resistance
Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D. L., DiPietro, L., Cline, G. W., & Shulman, G. I. (2003) · Science · doi:10.1126/science.1082889 · Cited by 2,107
Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone, R., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1032913100 · Cited by 1,952
Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z.-W., Karin, M., & Shoelson, S. E. (2001) · Science · doi:10.1126/science.1061620 · Cited by 1,884
Impaired immune and acute-phase responses in interleukin-6-deficient mice
Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., Zinkernagel, R., Bluethmann, H., & Köhler, G. (1994) · Nature · doi:10.1038/368339a0 · Cited by 1,768 · cited 2×
“The present data are in accordance with some [18, 41], but not all [17, 42] previous studies in IL-6-deficient mice.”
BackgroundResultPark, E. J., Lee, J. H., Yu, G.-Y., He, G., Ali, S. R., Holzer, R. G., Österreicher, C. H., Takahashi, H., & Karin, M. (2010) · Cell · doi:10.1016/j.cell.2009.12.052 · Cited by 1,764
Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice
Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furth, E. E., Poli, V., & Taub, R. (1996) · Science · doi:10.1126/science.274.5291.1379 · Cited by 1,538
Interleukin-6-deficient mice develop mature-onset obesity
Wallenius, V., Wallenius, K., Ahrén, B., Rudling, M., Carlsten, H., Dickson, S. L., Ohlsson, C., & Jansson, J.-O. (2002) · Nature Medicine · doi:10.1038/nm0102-75 · Cited by 1,213
Role of Mitochondrial Dysfunction in Insulin Resistance
Kim, J.-A., Wei, Y., & Sowers, J. R. (2008) · Circulation Research · doi:10.1161/circresaha.107.165472 · Cited by 1,103
Carey, A. L., Steinberg, G. R., Macaulay, S. L., Thomas, W. G., Holmes, A. G., Ramm, G., Prelovsek, O., Hohnen-Behrens, C., Watt, M. J., James, D. E., et al. (2006) · Diabetes · doi:10.2337/db05-1404 · Cited by 898
Interleukin-6 induces cellular insulin resistance in hepatocytes.
Senn, J. J., Klover, P. J., Nowak, I. A., & Mooney, R. A. (2002) · Diabetes · doi:10.2337/diabetes.51.12.3391 · Cited by 883 · cited 1×
“This conclusion is based on several observations demonstrating that exogenous administration of IL-6 impairs insulin signal transduction in the liver in vitro [36, 37] and in vivo [13].”
BackgroundMorino, K., Petersen, K. F., & Shulman, G. I. (2006) · Diabetes · doi:10.2337/db06-s002 · Cited by 853
Exercise and IL‐6 infusion inhibit endotoxin‐induced TNF‐α production in humans
Starkie, R., Ostrowski, S. R., Jauffred, S., Febbraio, M., & Pedersen, B. K. (2003) · The FASEB Journal · doi:10.1096/fj.02-0670fje · Cited by 790
Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis.
Pérez-Carreras, M., Del Hoyo, P., Martín, M. A., Rubio, J. C., Martín, A., Castellano, G., Colina, F., Arenas, J., & Solis-Herruzo, J. A. (2003) · Hepatology · doi:10.1002/hep.1840380426 · Cited by 734
How Obesity Causes Diabetes: Not a Tall Tale
Lazar, M. A. (2005) · Science · doi:10.1126/science.1104342 · Cited by 577
HSP72 protects against obesity-induced insulin resistance
Chung, J., Nguyen, A.-K., Henstridge, D. C., Holmes, A. G., Chan, M. H. S., Mesa, J. L., Lancaster, G. I., Southgate, R. J., Bruce, C. R., Duffy, S. J., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705799105 · Cited by 553
Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo
Kim, H.-J., Higashimori, T., Park, S.-Y., Choi, H., Dong, J., Kim, Y.-J., Noh, H.-L., Cho, Y.-R., Cline, G., Kim, Y.-B., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1060 · Cited by 534
PKC-θ knockout mice are protected from fat-induced insulin resistance
Kim, J. K., Fillmore, J. J., Sunshine, M. J., Albrecht, B., Higashimori, T., Kim, D.-W., Liu, Z.-X., Soos, T. J., Cline, G. W., O’Brien, W. R., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422230 · Cited by 500
Chronic Exposure to Interleukin-6 Causes Hepatic Insulin Resistance in Mice
Klover, P. J., Zimmers, T. A., Koniaris, L. G., & Mooney, R. A. (2003) · Diabetes · doi:10.2337/diabetes.52.11.2784 · Cited by 488
Pessayre, D., & Fromenty, B. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.03.004 · Cited by 441
The expression of adipogenic genes is decreased in obesity and diabetes mellitus
Nadler, S. T., Stoehr, J. P., Schueler, K. L., Tanimoto, G., Yandell, B. S., & Attie, A. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.21.11371 · Cited by 386
Bruce, C. R., Hoy, A. J., Turner, N., Watt, M. J., Allen, T. L., Carpenter, K., Cooney, G. J., Febbraio, M. A., & Kraegen, E. W. (2009) · Diabetes · doi:10.2337/db08-1078 · Cited by 363
Self-citationThe role of interleukins in insulin resistance and type 2 diabetes mellitus
Fève, B., & Bastard, J.-P. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.62 · Cited by 343
Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis
Pérez-Carreras, M. (2003) · Hepatology · doi:10.1053/jhep.2003.50398 · Cited by 340
Petersen, E. W., Carey, A. L., Sacchetti, M., Steinberg, G. R., Macaulay, S. L., Febbraio, M. A., & Pedersen, B. K. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00257.2004 · Cited by 311
Self-citationSolinas, G., Naugler, W., Galimi, F., Lee, M.-S., & Karin, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607626103 · Cited by 284
CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK
Watt, M. J., Dzamko, N. L., Thomas, W. G., Rose‐John, S., Ernst, M., Carling, D., Kemp, B. E., Febbraio, M. A., & Steinberg, G. R. (2006) · Nature Medicine · doi:10.1038/nm1383 · Cited by 282
Interleukin-6 depletion selectively improves hepatic insulin action in obesity.
Klover, P. J., Clementi, A. H., & Mooney, R. A. (2005) · Endocrinology · doi:10.1210/en.2004-1468 · Cited by 273
Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle
Al-Khalili, L., Bouzakri, K., Glund, S., Lönnqvist, F., Koistinen, H. A., & Krook, A. (2006) · Molecular Endocrinology · doi:10.1210/me.2005-0490 · Cited by 250
Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle
Glund, S., Deshmukh, A., Long, Y. C., Moller, T., Koistinen, H. A., Caidahl, K., Zierath, J. R., & Krook, A. (2007) · Diabetes · doi:10.2337/db06-1733 · Cited by 219
Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ
Lam, T. K. T., Yoshii, H., Haber, C. A., Bogdanovic, E., Lam, L., Fantus, I. G., & Giacca, A. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00038.2002 · Cited by 195
Mature-Onset Obesity in Interleukin-1 Receptor I Knockout Mice
García, M. C., Asterholm, I. W., Berndtsson, A., Enge, M., Bell, M., Hultgren, O., Horn, M., Åhrén, B., Enerbäck, S., Ohlsson, C., et al. (2006) · Diabetes · doi:10.2337/db05-1304 · Cited by 178
Bruce, C. R., & Dyck, D. J. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00150.2004 · Cited by 178
Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice
Franckhauser, S., Elias, I., Sopasakis, V. R., Ferré, T., Nagaev, I., Andersson, C. X., Agudo, J., Ruberte, J., Bosch, F., & Smith, U. (2008) · Diabetologia · doi:10.1007/s00125-008-0998-8 · Cited by 175
Carey, A. L., Bruce, C. R., Sacchetti, M., Anderson, M. J., Olsen, D. B., Saltin, B., Hawley, J. A., & Febbraio, M. A. (2004) · Diabetologia · doi:10.1007/s00125-004-1403-x · Cited by 168
Gregorio, G. B. D., Hensley, L. L., Lü, T., Ranganathan, G., & Kern, P. A. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00189.2003 · Cited by 165
Human IL6 enhances leptin action in mice
Sadagurski, M., Norquay, L., Farhang, J., D’Aquino, K. E., Copps, K. D., & White, M. F. (2009) · Diabetologia · doi:10.1007/s00125-009-1580-8 · Cited by 160
Interleukin-6 inhibits oxidative injury and necrosis after extreme liver resection
Jin, X., Zhang, Z., Beer–Stolz, D., Zimmers, T. A., & Koniaris, L. G. (2007) · Hepatology · doi:10.1002/hep.21728 · Cited by 85
Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes #
Henkel, J., Neuschäfer‐Rube, F., Pathe‐Neuschäfer‐Rube, A., & Püschel, G. P. (2009) · Hepatology · doi:10.1002/hep.23064 · Cited by 74
Holmes, A. G., Mesa, J. L., Neill, B., Chung, J. Z. Y., Carey, A. L., Steinberg, G. R., Kemp, B. E., Southgate, R. J., Lancaster, G. I., Bruce, C. R., et al. (2008) · Journal of Endocrinology · doi:10.1677/joe-08-0113 · Cited by 71
Is Interleukin-6 Receptor Blockade the Holy Grail for Inflammatory Diseases?
Febbraio, M. A., Rose‐John, S., & Pedersen, B. K. (2010) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2010.1 · Cited by 55
Yuen, D. Y. C., Dwyer, R. M., Matthews, V. B., Zhang, L., Drew, B. G., Neill, B., Kingwell, B. A., Clark, M. G., Rattigan, S., & Febbraio, M. A. (2009) · Diabetes · doi:10.2337/db08-0775 · Cited by 55
Sopasakis, V. R., Larsson, B.-M., Johansson, A., Holm�ng, A., & Smith, U. (2004) · Diabetologia · doi:10.1007/s00125-004-1544-y · Cited by 40
Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes
Fosgerau, K., Galle, P. R., Hansen, T. K., Albrechtsen, A., Rieper, C. D. L., Pedersen, B. K., Larsen, L. K., Thomsen, A. R., Pedersen, O. B., Hansen, M. B., et al. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0413 · Cited by 34
Cited by
Sorted by citations
Adipokines in inflammation and metabolic disease
Ouchi, N., Parker, J. L., Lugus, J. J., & Walsh, K. (2011) · Nature Reviews Immunology · doi:10.1038/nri2921 · Cited by 4,625
Type 2 diabetes as an inflammatory disease
Donath, M. Y., & Shoelson, S. E. (2011) · Nature Reviews Immunology · doi:10.1038/nri2925 · Cited by 3,737
The pro- and anti-inflammatory properties of the cytokine interleukin-6
Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.034 · Cited by 3,212
Macrophage Cytokines: Involvement in Immunity and Infectious Diseases
Arango Duque, G., & Descoteaux, A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00491 · Cited by 2,708
“The anti-inflammatory properties of IL-6 are illustrated by IL-6−/− mice, which exhibit hepatosteatosis, insulin resistance, and liver inflammation (44).”
BackgroundThe cellular and signaling networks linking the immune system and metabolism in disease
Osborn, O., & Olefsky, J. M. (2012) · Nature Medicine · doi:10.1038/nm.2627 · Cited by 1,551
Metadata
- Authors
- Matthews, V. B., Allen, T. L., Risis, S., Chan, M. H. S., Henstridge, D. C., Watson, N., Zaffino, L. A., Babb, J. R., Boon, J., Meikle, P. J., Jowett, J. B., Watt, M. J., Jansson, J.-O., Bruce, C. R., & Febbraio, M. A.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- Monash University (AU)
- University of Gothenburg (SE)
- Corresponding author
- Febbraio, M. A.
- ORCID
- Venue
- Diabetologia
- Published
- 2010-08-11
- Volume
- 53
- Issue
- 11
- Pages
- 2431-2441
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2089567564
- Cited by
- 334
- References
- 50
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 12 · 2023: 15 · 2022: 23 · 2021: 21 · 2020: 26 · 2019: 27 · 2018: 21 · 2017: 29 · 2016: 26 · 2015: 22 · 2014: 20 · 2013: 31 · 2012: 25
- FWCI
- 18.39
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Licence
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Figshare (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- interleukin-6, hepatic insulin resistance, liver inflammation, obesity, high-fat diet, hepatic steatosis, mitochondrial metabolism, oxidative phosphorylation, beta-hydroxyacyl-CoA dehydrogenase, mitochondrial respiratory chain, liver fat deposition
- MeSH terms
- Animals, Body Composition, Calorimetry, Indirect, Diglycerides, Fatty Liver, Female, Inflammation, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Obesity, Triglycerides, Interleukin-6, Adipocytes, Mice, Knockout, Cell Size, Adiposity, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
