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.
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IL-6−/− mice exhibit hepatosteatosis, insulin resistance, and liver inflammation.
“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 these same contexts, others have shown that IL6 induces insulin sensitivity, while IL6 has been shown to be insulin sensitizing in exercise.
“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
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 · see citing works
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 · see citing works
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199 · see citing works
Ghrelin induces adiposity in rodents
Tschöp, M., Smiley, D. L., & Heiman, M. L. (2000) · Nature · doi:10.1038/35038090 · Cited by 3,949 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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× · see citing works
“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 · see citing works
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 1,536 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Morino, K., Petersen, K. F., & Shulman, G. I. (2006) · Diabetes · doi:10.2337/db06-s002 · Cited by 853 · see citing works
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 · see citing works
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 · see citing works
How Obesity Causes Diabetes: Not a Tall Tale
Lazar, M. A. (2005) · Science · doi:10.1126/science.1104342 · Cited by 570 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Pessayre, D., & Fromenty, B. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.03.004 · Cited by 441 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis
Pérez-Carreras, M. (2003) · Hepatology · doi:10.1053/jhep.2003.50398 · Cited by 340 · see citing works
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 · see citing works
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 · see citing works
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 275 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Bruce, C. R., & Dyck, D. J. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00150.2004 · Cited by 178 · see citing works
Mature-Onset Obesity in Interleukin-1 Receptor I Knockout Mice
García, M. C., Asterholm, I. W., Berndtsson, A., Enge, M., Bell, M. I., Hultgren, O., Horn, M., Åhrén, B., Enerbäck, S., Ohlsson, C., et al. (2006) · Diabetes · doi:10.2337/db05-1304 · Cited by 174 · see citing works
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 170 · see citing works
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 166 · see citing works
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 161 · see citing works
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 161 · see citing works
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 · see citing works
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 73 · see citing works
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 70 · see citing works
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 · see citing works
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 · see citing works
Sopasakis, V. R., Larsson, B.-M., Johansson, A., Holm�ng, A., & Smith, U. (2004) · Diabetologia · doi:10.1007/s00125-004-1544-y · Cited by 39 · see citing works
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 32 · see citing works
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Ouchi, N., Parker, J. L., Lugus, J. J., & Walsh, K. (2011) · Nature Reviews Immunology · doi:10.1038/nri2921 · Cited by 4,625 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
Muscle–Organ Crosstalk: The Emerging Roles of Myokines
Severinsen, M. C. K., & Pedersen, B. K. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa016 · Cited by 1,226 · see citing works
“Systemic IL-6 knockout mice accumulate adipose tissue (106, 107), whereas central overexpression of IL-6 (116, 117) leads to a decrease in body weight, indicating that IL-6 is a player in body weight control.”
BackgroundRecent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer
Jones, S. A., & Jenkins, B. J. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0066-7 · Cited by 1,102 · see citing works
IL-6 pathway in the liver: From physiopathology to therapy
Schmidt-Arras, D., & Rose-John, S. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.02.004 · Cited by 881 · see citing works
Obesity, insulin resistance and free fatty acids
Boden, G. (2011) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e3283444b09 · Cited by 848 · see citing works
Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training
Roberts, C. K., Hevener, A. L., & Barnard, R. J. (2012) · Comprehensive physiology · doi:10.1002/cphy.c110062 · Cited by 919 · see citing works
Interleukin-6 Family Cytokines.Preprint
Rose-John, S. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028415 · Cited by 727 · see citing works
Physical activity and muscle-brain crosstalk
Pedersen, B. K. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0174-x · Cited by 772 · see citing works
Mauer, J., Chaurasia, B., Goldau, J., Vogt, M. C., Ruud, J., Nguyen, K. D., Theurich, S., Hausen, A. C., Schmitz, J., Brönneke, H. S., et al. (2014) · Nature Immunology · doi:10.1038/ni.2865 · Cited by 727 · see citing works
IL-6 and related cytokines as the critical lynchpins between inflammation and cancer
Taniguchi, K., & Karin, M. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.001 · Cited by 713 · see citing works
Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling
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Interleukin-6: designing specific therapeutics for a complex cytokine
Garbers, C., Heink, S., Korn, T., & Rose-John, S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.45 · Cited by 643 · see citing works
Versatile functions for IL-6 in metabolism and cancer
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Plasticity and cross-talk of Interleukin 6-type cytokines
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Plasma Lysophosphatidylcholine Levels Are Reduced in Obesity and Type 2 Diabetes
Barber, M., Risis, S., Yang, C., Meikle, P. J., Staples, M., Febbraio, M. A., & Bruce, C. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041456 · Cited by 370 · see citing works
Toll-like receptors: linking inflammation to metabolism
Könner, A. C., & Brüning, J. C. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.08.007 · Cited by 327 · see citing works
Origin and function of stress-induced IL-6 in murine models
Qing, H., Desrouleaux, R., Israni-Winger, K., Mineur, Y. S., Fogelman, N., Zhang, C., Rashed, S., Palm, N. W., Sinha, R., Picciotto, M. R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.054 · Cited by 303 · see citing works
IL-6 signalling pathways and the development of type 2 diabetes
Akbari, M., & Hassan‐Zadeh, V. (2018) · Inflammopharmacology · doi:10.1007/s10787-018-0458-0 · Cited by 304 · see citing works
Insulin signalling mechanisms for triacylglycerol storage
Czech, M., Tencerová, M., Pedersen, D. J., & Aouadi, M. (2013) · Diabetologia · doi:10.1007/s00125-013-2869-1 · Cited by 272 · see citing works
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From cytokine to myokine: The emerging role of interleukin-6 in metabolic regulation
Pal, M., Febbraio, M. A., & Whitham, M. (2014) · Immunology & Cell Biology · doi:10.1038/icb.2014.16 · Cited by 258 · see citing works
Emerging avenues linking inflammation and cancer
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Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., Matthews, V. B., Neill, B., White, D. A., Murphy, A. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.02.006 · Cited by 257 · see citing works
Adipose tissue inflammation in obesity: A metabolic or immune response?
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IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling
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Gehrke, N., & Schattenberg, J. M. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.02.020 · Cited by 211 · see citing works
Chen, Y., Bui, A. V., Diesch, J., Manasseh, R., Hausding, C., Rivera, J., Haviv, I., Agrotis, A., Htun, N., Jowett, J. B. M., et al. (2013) · Circulation Research · doi:10.1161/circresaha.113.301562 · Cited by 206 · see citing works
Henstridge, D. C., Bruce, C. R., Drew, B. G., Tory, K., Kolonics, A., Estevez, E., Chung, J., Watson, N., Gardner, T., Lee-Young, R. S., et al. (2014) · Diabetes · doi:10.2337/db13-0967 · Cited by 201 · see citing works
Metabolic inflammation: Connecting obesity and insulin resistance
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Immune and inflammatory pathways in NASH
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Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training
Roberts, C. K., Hevener, A. L., & Barnard, R. J. (2013) · Comprehensive physiology · doi:10.1002/j.2040-4603.2013.tb00484.x · Cited by 184 · see citing works
“Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis
Febbraio, M. A., & Karin, M. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.09.004 · Cited by 177 · see citing works
Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research
Willebrords, J., Pereira, I. V. A., Maes, M., Yanguas, S. C., Colle, I. O., Bossche, B. V. D., da Silva, T. C., de Oliveira, C. P. M. S., Andraus, W., Alves, V. A. F., et al. (2015) · Progress in Lipid Research · doi:10.1016/j.plipres.2015.05.002 · Cited by 172 · see citing works
Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity
Cropley, J. E., Eaton, S. A., Aiken, A., Young, P. E., Giannoulatou, E., Ho, J. W. K., Buckland, M. E., Keam, S. P., Hutvágner, G., Humphreys, D. T., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.008 · Cited by 171 · see citing works
IL ‐6 in diabetes and cardiovascular complications
Qu, D. C., Liu, J., Lau, C. W., & Huang, Y. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12713 · Cited by 162 · see citing works
New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
The exercise IL-6 enigma in cancer
Orange, S. T., Leslie, J., Ross, M., Mann, D. A., & Wackerhage, H. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.08.001 · Cited by 149 · see citing works
Toll-like receptors, inflammation, metabolism and obesity
Fresno, M., Álvarez, R., & Cuesta, N. (2011) · Archives of Physiology and Biochemistry · doi:10.3109/13813455.2011.562514 · Cited by 148 · see citing works
Drew, B. G., Ribas, V., Le, J. A., Henstridge, D. C., Phun, J., Zhou, Z., Soleymani, T., Daraei, P., Sitz, D., Vergnes, L., et al. (2014) · Diabetes · doi:10.2337/db13-0665 · Cited by 145 · see citing works
Interleukin-6 in inflammatory and malignant diseases of the pancreas
Lesina, M., Wörmann, S. M., Neuhöfer, P., Song, L., & Algül, H. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.002 · Cited by 146 · see citing works
Physiological effects of modulating the interleukin-6 axis
Schett, G. A. (2018) · Lara D. Veeken · doi:10.1093/rheumatology/kex513 · Cited by 143 · see citing works
Bruce, C. R., Risis, S., Babb, J. R., Yang, C., Kowalski, G. M., Selathurai, A., Lee, R. S., Weir, J. M., Yoshioka, K., Takuwa, Y., et al. (2012) · Diabetes · doi:10.2337/db12-0029 · Cited by 141 · see citing works
The biochemical alterations underlying post-burn hypermetabolism
Auger, C., Samadi, O., & Jeschke, M. G. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.02.019 · Cited by 138 · see citing works
IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease
Park, J., Zhao, Y., Zhang, F., Zhang, S., Kwong, A. C., Zhang, Y., Hoffmann, H.-H., Bushweller, L., Wu, X., Ashbrook, A. W., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2022.08.022 · Cited by 138 · see citing works
Shirazi, R. H., Pálsdóttir, V., Collander, J., Anesten, F., Vogel, H., Langlet, F., Jaschke, A., Schürmann, A., Prévot, V., Shao, R., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306799110 · Cited by 135 · see citing works
Obesity-related cognitive impairment: The role of endothelial dysfunction
Buie, J. N. J., Watson, L. S., Smith, C. J., & Sims‐Robinson, C. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104580 · Cited by 133 · see citing works
Gregersen, S., Samocha‐Bonet, D., Heilbronn, L. K., & Campbell, L. V. (2012) · Journal of Nutrition and Metabolism · doi:10.1155/2012/238056 · Cited by 136 · see citing works
Role of interleukins in obesity: implications for metabolic disease
Febbraio, M. A. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.02.004 · Cited by 130 · see citing works
Dong, J., Viswanathan, S., Adami, E., Singh, B. K., Chothani, S. P., Ng, B., Lim, W., Zhou, J., Tripathi, M., Ko, N. S. J., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20303-z · Cited by 130 · see citing works
Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages
Yu, H., Dilbaz, S., Coßmann, J., Hoang, A. C., Diedrich, V., Herwig, A., Harauma, A., Hoshi, Y., Moriguchi, T., Landgraf, K., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci125646 · Cited by 123 · see citing works
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 · see citing works
Caputo, T., Gilardi, F., & Desvergne, B. (2017) · FEBS Letters · doi:10.1002/1873-3468.12742 · Cited by 111 · see citing works
The metabolic syndrome: The crossroads between rheumatoid arthritis and cardiovascular risk
Gremese, E., & Ferraccioli, G. (2011) · Autoimmunity Reviews · doi:10.1016/j.autrev.2011.04.018 · Cited by 105 · see citing works
Pasquarelli-do-Nascimento, G., Braz-de-Melo, H. A., Faria, S. S., Santos, I. D. O., Kobinger, G., & Magalhães, K. G. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00530 · Cited by 99 · see citing works
Ikeda, S., Tamura, Y., Kakehi, S., Sanada, H., Kawamori, R., & Watada, H. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.03.159 · Cited by 100 · see citing works
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 · see citing works
Chiricozzi, A., Raimondo, A., Lembo, S., Fausti, F., Dini, V., Costanzo, A., Monfrecola, G., Balato, N., Ayala, F., Romanelli, M., et al. (2016) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2016.1201423 · Cited by 97 · see citing works
Diet-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 · see citing works
Self-citationMubarak, A., Hodgson, J. M., Considine, M. J., Croft, K. D., & Matthews, V. B. (2013) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf400920x · Cited by 92 · see citing works
Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice
Lindegaard, B., Matthews, V. B., Brandt, C., Højman, P., Allen, T. L., Estévez, E., Watt, M. J., Bruce, C. R., Mortensen, O. H., Syberg, S., et al. (2013) · Diabetes · doi:10.2337/db12-1095 · Cited by 91 · see citing works
Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice
Varma, A., Das, A., Hoke, N. N., Durrant, D., Salloum, F. N., & Kukreja, R. C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045243 · Cited by 90 · see citing works
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 · see citing works
Interleukin-6 in Schizophrenia—Is There a Therapeutic Relevance?
Borovčanin, M., Jovanović, I., Radosavljevic, G. D., Pantic, J. M., Janicijevic, S. M., Arsenijević, N., & Lukić, M. L. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00221 · Cited by 91 · see citing works
Signaling 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 87 · see citing works
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 88 · see citing works
Chuang, H., Sheu, W. H., Lin, Y.-T., Tsai, C.-Y., Yang, C. Y., Cheng, Y.-J., Huang, P. Y., Li, J.-P., Chiu, L.-L., Wang, X., et al. (2014) · Nature Communications · doi:10.1038/ncomms5602 · Cited by 88 · see citing works
Treatment of type 2 diabetes with the designer cytokine IC7Fc
Findeisen, M., Allen, T. L., Henstridge, D. C., Kammoun, H., Brandon, A. E., Baggio, L. L., Watt, K. I., Pal, M., Cron, L., Estevez, E., et al. (2019) · Nature · doi:10.1038/s41586-019-1601-9 · Cited by 86 · see citing works
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 84 · see citing works
Li, C. C. Y., Young, P. E., Maloney, C., Eaton, S. A., Cowley, M. J., Buckland, M. E., Preiß, T., Henstridge, D. C., Cooney, G. J., Febbraio, M. A., et al. (2013) · Epigenetics · doi:10.4161/epi.24656 · Cited by 82 · see citing works
Hitting a complex target: an update on interleukin-6 trans-signalling
Waetzig, G. H., & Rose-John, S. (2012) · Expert opinion on therapeutic targets · doi:10.1517/14728222.2012.660307 · Cited by 96 · see citing works
Palmitate and insulin synergistically induce IL-6 expression in human monocytes
Bunn, R. C., Cockrell, G. E., Ou, Y., Thrailkill, K. M., Lumpkin, C. K., & Fowlkes, J. L. (2010) · Cardiovascular Diabetology · doi:10.1186/1475-2840-9-73 · Cited by 82 · see citing works
Tarantino, G. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i40.6735 · Cited by 81 · see citing works
Genetically modified mouse models for the study of nonalcoholic fatty liver disease
Nagarajan, P. (2012) · World Journal of Gastroenterology · doi:10.3748/wjg.v18.i11.1141 · Cited by 79 · see citing works
Mishra, D., Richard, J. E., Marić, I., Porteiro, B., Häring, M., Kooijman, S., Musovic, S., Eerola, K., López‐Ferreras, L., Peris, E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.044 · Cited by 80 · see citing works
Exercise increases pancreatic β‐cell viability in a model of type 1 diabetes through IL‐6 signaling
de Paula, F. M. M., Leite, N. C., Vanzela, E. C., Kurauti, M. A., Dias, R. D. F., Carneiro, E. M., Boschero, A. C., & Zoppi, C. C. (2015) · The FASEB Journal · doi:10.1096/fj.14-264820 · Cited by 78 · see citing works
Nicholls, H. T., Kowalski, G. M., Kennedy, D. J., Risis, S., Zaffino, L. A., Watson, N., Kanellakis, P., Watt, M. J., Bobik, A., Bonen, A., et al. (2011) · Diabetes · doi:10.2337/db10-1353 · Cited by 77 · see citing works
Pimentel, G. D., Lira, F. S., Neto, J. C. R., Caris, A. V., Pinheiro, F., Ribeiro, E. B., do Nascimento, C. M. O., & Oyama, L. M. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2012.04.016 · Cited by 76 · see citing works
Komori, T., Tanaka, M., Senba, E., Miyajima, A., & Morikawa, Y. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.461905 · Cited by 72 · see citing works
Roles of Chronic Low-Grade Inflammation in the Development of Ectopic Fat Deposition
Liu, L., Mei, M., Yang, S., & Li, Q. (2014) · Mediators of Inflammation · doi:10.1155/2014/418185 · Cited by 71 · see citing works
Deficiency 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 · see citing works
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 68 · see citing works
The 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 · see citing works
Beringer, A., Thiam, N. N., Molle, J., Bartosch, B., & Miossec, P. (2018) · Clinical & Experimental Immunology · doi:10.1111/cei.13140 · Cited by 68 · see citing works
Trobec, K. Č., von Haehling, S., Anker, S. D., & Lainščak, M. (2011) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-011-0043-5 · Cited by 68 · see citing works
NCOA5 Haploinsufficiency Results in Glucose Intolerance and Subsequent Hepatocellular Carcinoma
Gao, S., Li, A., Liu, F., Chen, F., Williams, M., Zhang, C., Kelley, Z., Wu, C., Luo, R., & Xiao, H. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.11.005 · Cited by 67 · see citing works
Henstridge, D. C., Bruce, C. R., Pang, C. P., Lancaster, G. I., Allen, T. L., Estévez, E., Gardner, T., Weir, J. M., Meikle, P. J., Lam, K. S. L., et al. (2012) · Diabetologia · doi:10.1007/s00125-012-2652-8 · Cited by 67 · see citing works
Ahmad, B., Vohra, M. S., Saleemi, M. A., Serpell, C. J., Fong, I. L., & Wong, E. H. (2021) · Biochimie · doi:10.1016/j.biochi.2021.01.015 · Cited by 64 · see citing works
Adipose tissue insulin action and IL-6 signaling after exercise in obese mice
MACPHERSON, R. E. K., HUBER, J. S., FRENDO-CUMBO, S., SIMPSON, J. A., & WRIGHT, D. C. (2015) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000000660 · Cited by 62 · see citing works
Pelt, D. W. V., Pitchford, L. M., & Horowitz, J. F. (2017) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00614.2017 · Cited by 60 · see citing works
A minor role for lipocalin 2 in high-fat diet-induced glucose intolerance
Jun, L. S., Siddall, P., & Rosen, E. D. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00147.2011 · Cited by 62 · see citing works
Metabolic control and sex: A focus on inflammatory‐linked mediators
Henstridge, D. C., Abildgaard, J., Lindegaard, B., & Febbraio, M. A. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14642 · Cited by 64 · see citing works
Segovia, S. A., Vickers, M. H., & Reynolds, C. M. (2017) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174417000204 · Cited by 62 · see citing works
Merry, T. L., Brooks, A. E. S., Masson, S. W. C., Adams, S. E., Jaiswal, J. K., Jamieson, S. M. F., & Shepherd, P. R. (2019) · International Journal of Obesity · doi:10.1038/s41366-019-0355-7 · Cited by 60 · see citing works
Exercise and health — emerging roles of IL-6
Ellingsgaard, H., Højman, P., & Pedersen, B. K. (2019) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.03.009 · Cited by 60 · see citing works
- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Epidemiology › 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
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