Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Open accessAbstract
We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Il6, Spp1, and Igfbp1 are involved in hepatic insulin resistance.
“genes reported to be involved in hepatic insulin resistance, including Il6 45-48 , Spp1 49,50 and Igfbp1 51”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [48]
Inhibition or inactivation of JNK or IKK improves insulin sensitivity in various insulin-resistant models and reduces inhibitory IRS-1 serine phosphorylation.
“In contrast, inhibition or inactivation of JNK (18,26) or IKK (22,24,25,27) improves insulin sensitivity in various models of insulin resistance in association with reduced inhibitory serine phosphorylation of IRS-1 (18).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [25]
Many insulin-resistant states, including obesity, type 2 diabetes, and lipid/heparin infusion, are associated with increased JNK and/or IKK activation together with inhibitory IRS-1 serine phosphorylation.
“Along these lines, numerous insulin-resistant states (e.g., obesity, type 2 diabetes, and lipid/heparin infusion) are associated with increased activation of JNK (18,21) and/or IKK (21)(22)(23)(24)(25) in parallel with inhibitory serine phosphorylation of IRS-1 (18,21).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [25]
JNK and IKK signaling are upregulated and activated in insulin-resistant human and rodent skeletal muscle.
“JNK (18,21) and IKK (22,25) signaling are upregulated and activated in insulin-resistant human and rodent skeletal muscle.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [25]
Knockout or inhibition of JNK1 or IKKβ prevents insulin resistance in cell and mouse models and in human models of insulin resistance.
“Accordingly, KO or inhibition of JNK1 or IKKβ prevents insulin resistance in cell and mouse models (18,22,24,25,87) as well as human models (27) of insulin resistance.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [25]
Inhibiting NF-κB improves hepatic insulin sensitivity.
“On the other hand, inhibition of NF-κB (25) or knockout of IKKβ in the hepatocyte (24) improves hepatic insulin sensitivity, indicating that when intrahepatocyte inflammatory pathways are blocked, the ability of the paracrine effects of activated Kupffer cells to cause liver insulin resistance is attenuated.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [25]
Hepatocyte-specific overexpression of IKKβ in mice causes hepatic insulin resistance.
“Consistent with this idea, primary genetic activation of inflammatory pathways within hepatocytes via hepatocyte-specific overexpression of IKKβ in mice causes hepatic insulin resistance (25).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [25]
Mice with genetically activated Iκ kinase β-nuclear factor-κB pathway in the liver developed both hepatic and peripheral insulin resistance.
“These mice developed both hepatic and peripheral insulin resistance.”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [126]
Cai and colleagues showed the potential for inflammation to cause insulin resistance by genetically activating the Iκ kinase β-nuclear factor-κB pathway specifically in the livers of mice.
“Cai and colleagues126 showed the potential for inflammation to cause insulin resistance by genetically activating this pathway specifically in the livers of mice.”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [126]
The insulin resistance in mice with hepatic activation of the Iκ kinase β-nuclear factor-κB pathway was ameliorated with salicylates.
“Moreover, the insulin resistance was ameliorated with salicylates, which also protected against insulin resistance in rodents after acute lipid infusion,127 and reversed insulin resistance in people with type 2 diabetes mellitus.128”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [126]
In cultured hepatocytes, preadipocytes, and mature adipocytes, IL-6 directly impairs insulin action.
“In cultured hepatocytes (25)(26)(27)(28), preadipocytes, and mature adipocytes (29), IL-6 directly impairs insulin action.”
From Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle (2006) · cites this paper as [26]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Starnes, H. F., Pearce, M. K., Tewari, A., Yim, J. H., Zou, J. C., & Abrams, J. S. (1990) · The Journal of Immunology · doi:10.4049/jimmunol.145.12.4185 · Cited by 322 · see citing works
RetractedObesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · see citing works
Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance
Hotamisligil, G. S., Shargill, N. S., & Spiegelman, B. M. (1993) · Science · doi:10.1126/science.7678183 · Cited by 7,518 · see citing works
Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319451 · Cited by 6,760 · see citing works
Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001
Mokdad, A. H., Ford, E. S., Bowman, B. A., Dietz, W. H., Vinicor, F., Bales, V. S., & Marks, J. S. (2003) · JAMA · doi:10.1001/jama.289.1.76 · Cited by 5,866 · see citing works
C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus
Pradhan, A. D. (2001) · JAMA · doi:10.1001/jama.286.3.327 · Cited by 4,433 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Kim, H. J., Park, S. Y., Choi, Y. J., Han, S. J., Lee, K. W., & Kim, D. J. (2013) · Hormone Research in Paediatrics · doi:10.1159/000348848 · Cited by 3,061 · see citing works
Suppression of TNF-α-Induced Apoptosis by NF-κB
Antwerp, D. J. V., Martin, S. J., Kafri, T., Green, D. R., & Verma, I. M. (1996) · Science · doi:10.1126/science.274.5288.787 · Cited by 2,581 · 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
Self-citationInflammatory Cytokines and the Risk to Develop Type 2 Diabetes
Spranger, J., Kroke, A., Möhlig, M., Hoffmann, K., Bergmann, M. M., Ristow, M., Boeing, H., & Pfeiffer, A. F. H. (2003) · Diabetes · doi:10.2337/diabetes.52.3.812 · Cited by 1,493 · see citing works
IKKβ/NF-κB Activation Causes Severe Muscle Wasting in Mice
Cai, D., Frantz, J. D., Tawa, N. E., Melendez, P. A., Oh, B.-C., Lidov, H. G. W., Hasselgren, P.-O., Frontera, W. R., Lee, J., Glass, D. J., et al. (2004) · Cell · doi:10.1016/j.cell.2004.09.027 · Cited by 1,367 · see citing works
Self-citationBoden, G., & Shulman, G. I. (2002) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.32.s3.3.x · Cited by 1,300 · see citing works
Rotter, V., Nagaev, I., & Smith, U. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301977200 · Cited by 1,062 · see citing works
Festa, A., D’Agostino, R., Tracy, R. P., & Haffner, S. M. (2002) · Diabetes · doi:10.2337/diabetes.51.4.1131 · Cited by 1,057 · see citing works
Is Type II diabetes mellitus a disease of the innate immune system?
Pickup, J. C., & Crook, M. A. (1998) · Diabetologia · doi:10.1007/s001250051058 · Cited by 1,040 · see citing works
Positive and Negative Regulation of IκB Kinase Activity Through IKKβ Subunit Phosphorylation
Delhase, M., Hayakawa, M., Chen, Y., & Karin, M. (1999) · Science · doi:10.1126/science.284.5412.309 · Cited by 852 · see citing works
Neuschwander‐Tetri, B. A., Brunt, E. M., Wehmeier, K. R., Oliver, D., & Bacon, B. R. (2003) · Hepatology · doi:10.1053/jhep.2003.50420 · Cited by 749 · see citing works
Prevention of fat-induced insulin resistance by salicylate
Kim, J. K., Kim, Y.-J., Fillmore, J. J., Chen, Y., Moore, I., Lee, J., Yuan, M., Li, Z. W., Karin, M., Perret, P., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11559 · Cited by 737 · see citing works
A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis
Promrat, K., Lutchman, G., Uwaifo, G. I., Freedman, R. J., Soza, A., Heller, T., Doo, E., Ghany, M., Premkumar, A., Park, Y., et al. (2004) · Hepatology · doi:10.1002/hep.20012 · Cited by 726 · cited 1× · see citing works
“We isolated IKK complexes from mouse liver lysates using anti-IKK-γ antibodies (PharMingen) coupled to protein A-Sepharose, and conducted in vitro kinase assays at 30 °C by adding [γ-32P]ATP and 2 μg of GST-IκBα (1-54)12.”
MethodIntrons increase transcriptional efficiency in transgenic mice.
Brinster, R. L., Allen, J. M., Behringer, R. R., Gelinas, R. E., & Palmiter, R. D. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.3.836 · Cited by 721 · see citing works
Potential Role of TNF-α in the Pathogenesis of Insulin Resistance and Type 2 Diabetes
Moller, D. E. (2000) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(00)00272-1 · Cited by 718 · see citing works
Inflammatory pathways and insulin action
Hotamisligil, G. S. (2003) · International Journal of Obesity · doi:10.1038/sj.ijo.0802502 · Cited by 717 · see citing works
Metformin in non-alcoholic steatohepatitis.
Marchesini, G., Bianchi, G., Tomassetti, S., Zoli, M., & Melchionda, N. (2001) · The Lancet · doi:10.1016/s0140-6736(01)06042-1 · Cited by 682 · see citing works
Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
Hundal, R. S., Petersen, K. F., Mayerson, A. B., Randhawa, P. S., Inzucchi, S. E., Shoelson, S. E., & Shulman, G. I. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14955 · Cited by 623 · see citing works
Self-citationMechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
Hundal, R. S., Petersen, K. F., Mayerson, A. B., Randhawa, P. S., Inzucchi, S., Shoelson, S. E., & Shulman, G. I. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214955 · Cited by 557 · see citing works
Self-citationFeinstein, R., Kanety, H., Papa, M. Z., Lunenfeld, B., & Karasik, A. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74276-8 · Cited by 550 · see citing works
NF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176
Lei, L., Cao, Z., & Goeddel, D. V. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.7.3792 · Cited by 536 · 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
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
Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance
Shoelson, S. E., Lee, J., & Yuan, M. (2003) · International Journal of Obesity · doi:10.1038/sj.ijo.0802501 · Cited by 474 · see citing works
Self-citationRyysy, L., Häkkinen, A. M., Goto, T., Vehkavaara, S., Westerbacka, J., Halavaara, J., & Yki-Järvinen, H. (2000) · Diabetes · doi:10.2337/diabetes.49.5.749 · Cited by 431 · see citing works
Kelley, D. E., McKolanis, T. M., Hegazi, R. A. F., Kuller, L. H., & Kalhan, S. C. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00117.2003 · Cited by 426 · see citing works
Lagathu, C., Bastard, J.-P., Auclair, M., Maachi, M., Capeau, J., & Caron, M. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.10.013 · Cited by 385 · see citing works
Abrams, J. S., Roncarolo, M., Yssel, H., Andersson, U., Gleich, G. J., & Silver, J. E. (1992) · Immunological Reviews · doi:10.1111/j.1600-065x.1992.tb01406.x · Cited by 347 · see citing works
Phosphorylation of IκBα Precedes but Is Not Sufficient for Its Dissociation from NF-κB
DiDonato, J. A., Mercurio, F., & Karin, M. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.3.1302 · Cited by 337 · see citing works
Troglitazone action is independent of adipose tissue.
Burant, C., Sreenan, S., Hirano, K., Tai, T. A., Lohmiller, J. J., Lukens, J. N., Davidson, N. O., Ross, S. R., & Graves, R. A. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119839 · Cited by 333 · see citing works
IκB Kinase (IKK)-Associated Protein 1, a Common Component of the Heterogeneous IKK Complex
Mercurio, F., Murray, B. W., Shevchenko, A., Bennett, B. L., Young, D. B., Li, J. W., Pascual, G., Motiwala, A., Zhu, H., Mann, M., et al. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.2.1526 · Cited by 325 · see citing works
Insulin Sensitivity and Its Measurement: Structural Commonalities among the Methods1
Radziuk, J. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.12.7025 · Cited by 289 · see citing works
Seppala-Lindroos, A. (2002) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.7.3023 · Cited by 168 · see citing works
Kanemaki, T., Kitade, H., Kaibori, M., Sakitani, K., 平松, 義., Kamiyama, Y., Ito, S., & Okumura, T. (1998) · Hepatology · doi:10.1002/hep.510270515 · Cited by 132 · see citing works
Conditional disruption of IκB kinase 2 fails to prevent obesity-induced insulin resistance
Röhl, M., Pasparakis, M., Baudler, S., Baumgartl, J., Gautam, D., Huth, M., Lorenzi, R. D., Krone, W., Rajewsky, K., & Brüning, J. C. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18712 · Cited by 103 · see citing works
Conditional disruption of IκB kinase 2 fails to prevent obesity-induced insulin resistance
Röhl, M., Pasparakis, M., Baudler, S., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200418712 · Cited by 81 · see citing works
[25] Signaling pathways leading to nuclear factor-κB activation
Li, N., & Karin, M. (2000) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(00)19027-5 · Cited by 48 · see citing works
Ebstein, W. (2002) · PubMed · Cited by 30 · see citing works
Shoelson, S. E. (2002) · Journal of Molecular Medicine · doi:10.1007/s00109-002-0383-x · Cited by 30 · see citing works
Self-citationBarzilaym, J. I., & Freedland, E. S. (2003) · Metabolic Syndrome and Related Disorders · doi:10.1089/154041903321648252 · Cited by 25 · see citing works
Shoelson, S. E. (2002) · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- [2]National Diabetes Data Group . Diabetes in America. 2nd National Institutes of Diabetes and Digestive Diseases, National Institutes of Health; Bethesda, Maryland: 1995. [Google Scholar]
- [45]Weibel ER. Academic Press; London: 1979. Sterelogical Methods. [Google Scholar]
Cited by
Sorted by citations
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199 · see citing works
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769 · see citing works
Self-citationInflammation, stress, and diabetes
Wellen, K. E., & Hotamisligil, G. S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25102 · Cited by 4,143 · see citing works
Inflammatory Mechanisms in Obesity
Gregor, M. F., & Hotamisligil, G. S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101322 · Cited by 3,754 · 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
Self-citationTLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690 · see citing works
The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)
Buzzetti, E., Pinzani, M., & Tsochatzis, E. A. (2016) · Metabolism · doi:10.1016/j.metabol.2015.12.012 · Cited by 3,119 · see citing works
Critical nodes in signalling pathways: insights into insulin action
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1837 · Cited by 2,760 · see citing works
Macrophages, inflammation, and insulin resistance
Olefsky, J. M., & Glass, C. K. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135846 · Cited by 2,733 · see citing works
Adipose tissue, adipokines, and inflammation
Fantuzzi, G. (2005) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2005.02.023 · Cited by 2,606 · see citing works
DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611 · see citing works
Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis
Tilg, H., & Moschen, A. R. (2010) · Hepatology · doi:10.1002/hep.24001 · Cited by 2,548 · see citing works
Cani, P. D., Possemiers, S., Van de Wiele, T., Guiot, Y., Everard, A., Rottier, O., Geurts, L., Naslain, D., Neyrinck, A., Lambert, D. M., et al. (2009) · Gut · doi:10.1136/gut.2008.165886 · Cited by 2,518 · 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
Inflammatory links between obesity and metabolic disease
Lumeng, C. N., & Saltiel, A. R. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57132 · Cited by 2,319 · see citing works
Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., Lee, J., Goldfine, A. B., Benoist, C., Shoelson, S., et al. (2009) · Nature Medicine · doi:10.1038/nm.2002 · Cited by 2,145 · see citing works
Self-citationObesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications
Fabbrini, E., Sullivan, S., & Klein, S. (2010) · Hepatology · doi:10.1002/hep.23280 · Cited by 2,100 · see citing works
Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes
Esser, N., Legrand-Poels, S., Piette, J., Scheen, A. J., & Paquot, N. (2014) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2014.04.006 · Cited by 1,981 · see citing works
NF-κB, Inflammation, and Metabolic Disease
Baker, R. G., Hayden, M. S., & Ghosh, S. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2010.12.008 · Cited by 1,952 · see citing works
Obesity, Inflammation, and Insulin Resistance
Shoelson, S. E., Herrero, L., & Naaz, A. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.059 · Cited by 1,806 · see citing works
Self-citationIKK-β links inflammation to obesity-induced insulin resistance
Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z.-W., Long, J. M., Wynshaw-Boris, A., Poli, G., Olefsky, J., & Karin, M. (2005) · Nature Medicine · doi:10.1038/nm1185 · Cited by 1,773 · see citing works
Shin, N.-R., Lee, J.-C., Lee, H.-Y., Kim, M.-S., Whon, T. W., Lee, M.-S., & Bae, J.-W. (2014) · Gut · doi:10.1136/gutjnl-2012-303839 · Cited by 1,550 · see citing works
Self-citationThe 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
CCR2 modulates inflammatory and metabolic effects of high-fat feeding
Weisberg, S. P., Hunter, D., Huber, R., Lemieux, J., Slaymaker, S., Vaddi, K., Charo, I., Leibel, R. L., & Jr., A. W. F. (2006) · Journal of Clinical Investigation · doi:10.1172/jci24335 · Cited by 1,497 · see citing works
Impact of the gut microbiota on inflammation, obesity, and metabolic disease
Boulangé, C. L., Neves, A. L., Chilloux, J., Nicholson, J. K., & Dumas, M.-E. (2016) · Genome Medicine · doi:10.1186/s13073-016-0303-2 · Cited by 1,438 · see citing works
Visceral fat adipokine secretion is associated with systemic inflammation in obese humans
Fontana, L., Eagon, J. C., Trujillo, M. E., Scherer, P. E., & Klein, S. (2007) · Diabetes · doi:10.2337/db06-1656 · Cited by 1,417 · see citing works
Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., & Cai, D. (2008) · Cell · doi:10.1016/j.cell.2008.07.043 · Cited by 1,350 · see citing works
Self-citationNF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma
Luedde, T., & Schwabe, R. F. (2011) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.213 · Cited by 1,345 · see citing works
Pathogenesis of type 2 diabetes mellitus
DeFronzo, R. A. (2004) · Medical Clinics of North America · doi:10.1016/j.mcna.2004.04.013 · Cited by 1,342 · see citing works
Macrophage-mediated inflammation in metabolic disease
Chawla, A., Nguyen, K. D., & Goh, Y. P. S. (2011) · Nature reviews. Immunology · doi:10.1038/nri3071 · Cited by 1,314 · see citing works
Protein degradation by the ubiquitin-proteasome pathway in normal and disease states
Lecker, S. H., Goldberg, A. L., & Mitch, W. E. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006010083 · Cited by 1,234 · see citing works
Insulin sensitivity: Modulation by nutrients and inflammation
Schenk, S., Saberi, M., & Olefsky, J. M. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34260 · Cited by 1,191 · 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
Lipid-induced insulin resistance: unravelling the mechanism
Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60408-4 · Cited by 1,189 · see citing works
The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus
Eizirik, D. L., Cardozo, A. K., & Cnop, M. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0015 · Cited by 1,173 · see citing works
Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes
Muoio, D. M., & Newgard, C. B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2327 · Cited by 1,177 · see citing works
Inflammation and insulin resistance
de Luca, C., & Olefsky, J. M. (2008) · FEBS Letters · doi:10.1016/j.febslet.2007.11.057 · Cited by 1,161 · 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
Creely, S. J., McTernan, P. G., Kusminski, C. M., Fisher, F. M., Da Silva, N. F., Khanolkar, M., Evans, M., Harte, A. L., & Kumar, S. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00302.2006 · Cited by 1,043 · see citing works
Lumeng, C. N., DeYoung, S. M., Bodzin, J. L., & Saltiel, A. R. (2007) · Diabetes · doi:10.2337/db06-1076 · Cited by 1,016 · see citing works
Tilg, H., Moschen, A. R., & Roden, M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.147 · Cited by 1,002 · see citing works
The role of the gut microbiota in energy metabolism and metabolic disease
Cani, P., & Delzenne, N. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788168164 · Cited by 974 · see citing works
Oxidative stress in obesity: A critical component in human diseases
Marseglia, L., Manti, S., D’Angelo, G., Nicotera, A., Parisi, E., Di Rosa, G., Gitto, E., & Arrigo, T. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms16010378 · Cited by 933 · see citing works
Trends in insulin resistance: insights into mechanisms and therapeutic strategy
Li, M., Chi, X., Wang, Y., Setrerrahmane, S., Xie, W., & Xu, H. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01073-0 · Cited by 939 · see citing works
Nonalcoholic Fatty Liver Disease: Pathology and Pathogenesis
Tiniakos, D. G., Vos, M. B., & Brunt, E. M. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102132 · Cited by 870 · 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
Reactive oxygen species in health and disease
Alfadda, A. A., & Sallam, R. M. (2012) · Journal of Biomedicine and Biotechnology · doi:10.1155/2012/936486 · Cited by 824 · see citing works
Inflammatory mechanisms in the regulation of insulin resistance
Tilg, H., & Moschen, A. R. (2008) · Molecular Medicine · doi:10.2119/2007-00119.tilg · Cited by 779 · 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
The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer
Naugler, W. E., & Karin, M. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.12.007 · Cited by 730 · 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
Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue
Kosteli, A., Sugaru, E., Haemmerle, G., Martin, J. F., Lei, J., Zechner, R., & Ferrante, A. W. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42845 · Cited by 726 · see citing works
Obesity in Pregnancy Stimulates Macrophage Accumulation and Inflammation in the Placenta
Challier, J. C., Basu, S., Bintein, T., Minium, J., Hotmire, K., Catalano, P. M., & Hauguel-de Mouzon, S. (2008) · Placenta · doi:10.1016/j.placenta.2007.12.010 · Cited by 712 · see citing works
Adipocytokines in Obesity and Metabolic Disease
Cao, H. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0339 · Cited by 705 · see citing works
Defining high-fat-diet rat models: Metabolic and molecular effects of different fat types
Buettner, R., Parhofer, K. G., Woenckhaus, M., Wrede, C. E., Kunz-Schughart, L. A., Schölmerich, J., & Bollheimer, L. C. (2006) · Journal of Molecular Endocrinology · doi:10.1677/jme.1.01909 · Cited by 704 · see citing works
Holland, W. L., Bikman, B. T., Wang, L.-P., Yuguang, G., Sargent, K. M., Bulchand, S., Knotts, T. A., Shui, G., Clegg, D. J., Wenk, M. R., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43378 · Cited by 705 · see citing works
Mechanisms of insulin resistance in obesity
Ye, J. (2013) · Frontiers of Medicine · doi:10.1007/s11684-013-0262-6 · Cited by 699 · see citing works
Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Foretz, M., Guigas, B., & Viollet, B. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0242-2 · Cited by 686 · see citing works
Akash, M. S. H., Rehman, K., & Liaqat, A. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26174 · Cited by 690 · see citing works
Alternative macrophage activation and metabolism
Odegaard, J. I., & Chawla, A. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130138 · Cited by 640 · see citing works
Cancello, R., Tordjman, J., Poitou, C., Guilhem, G., Bouillot, J. L., Hugol, D., Coussieu, C., Basdevant, A., Hen, A. B., Bedossa, P., et al. (2006) · Diabetes · doi:10.2337/db06-0133 · Cited by 607 · see citing works
Increased Hepatic and Circulating Interleukin-6 Levels in Human Nonalcoholic Steatohepatitis
Wieckowska, A., Papouchado, B. G., Li, Z., Lopez, R., Zein, N. N., & Feldstein, A. E. (2008) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2007.01774.x · Cited by 597 · see citing works
Phosphorylation of IRS proteins, insulin action, and insulin resistance
Boura-Halfon, S., & Zick, Y. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90437.2008 · Cited by 598 · see citing works
Toll-Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Induced Obesity
Kim, F., Pham, M., Luttrell, I., Bannerman, D. D., Tupper, J., Thaler, J., Hawn, T. R., Raines, E. W., & Schwartz, M. W. (2007) · Circulation Research · doi:10.1161/circresaha.106.142851 · Cited by 584 · see citing works
The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance
Goossens, G. H. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.10.010 · Cited by 591 · see citing works
Korenblat, K. M., Fabbrini, E., Mohammed, B. S., & Klein, S. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.01.075 · Cited by 592 · see citing works
Rausch, M. E., Weisberg, S., Vardhana, P., & Tortoriello, D. V. (2008) · International Journal of Obesity · doi:10.1038/sj.ijo.0803744 · Cited by 585 · 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
Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer
Hart, P. A., Bellin, M. D., Andersen, D. K., Bradley, D., Cruz-Monserrate, Z., Forsmark, C. E., Goodarzi, M. O., Habtezion, A., Korc, M., Kudva, Y. C., et al. (2016) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(16)30106-6 · Cited by 551 · see citing works
Glucocorticoids, metabolism and metabolic diseases
Vegiopoulos, A., & Herzig, S. (2007) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.05.015 · Cited by 535 · see citing works
Molecular Mechanisms and Clinical Implications of Reversible Protein <i>S</i> -Glutathionylation
Mieyal, J. J., Gallogly, M. M., Qanungo, S., Sabens, E. A., & Shelton, M. D. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2008.2089 · Cited by 523 · see citing works
Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., Xiang, X., Luo, Z., & Ruderman, N. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3458 · Cited by 528 · see citing works
An official European Respiratory Society statement on physical activity in COPD
Watz, H., Pitta, F., Rochester, C. L., Garcia-Aymerich, J., ZuWallack, R., Troosters, T., Vaes, A. W., Puhan, M. A., Jehn, M., Polkey, M. I., et al. (2014) · European Respiratory Journal · doi:10.1183/09031936.00046814 · Cited by 526 · see citing works
The role of hepatokines in metabolism
Stefan, N., & Häring, H.-U. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.258 · Cited by 500 · see citing works
Kleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.08.013 · Cited by 483 · see citing works
Obesity and cancer risk: the role of the insulin-IGF axis
Renehan, A. G., Frystyk, J., & Flyvbjerg, A. (2006) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2006.08.006 · Cited by 480 · see citing works
Hevener, A. L., Olefsky, J. M., Reichart, D., Nguyen, M. T. A., Bandyopadyhay, G., Leung, H.-Y., Watt, M. J., Benner, C., Febbraio, M. A., Nguyen, A.-K., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31561 · Cited by 459 · see citing works
NAFLD as a driver of chronic kidney disease
Byrne, C. D., & Targher, G. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.01.013 · Cited by 449 · see citing works
Physical activity and modulation of systemic low-level inflammation
Bruunsgaard, H. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0505247 · Cited by 429 · see citing works
Tanti, J.-F., & Jager, J. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.07.004 · Cited by 430 · see citing works
Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer
Cani, P. D., & Jordan, B. F. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0025-6 · Cited by 383 · 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
The metabolic syndrome: role of skeletal muscle metabolism.
Stump, C. S., Henriksen, E. J., Wei, Y., & Sowers, J. R. (2006) · Annals of Medicine · doi:10.1080/07853890600888413 · Cited by 362 · see citing works
Kim, F., Pham, M., Maloney, E., Rizzo, N. O., Morton, G. J., Wisse, B. E., Kirk, E. A., Chait, A., & Schwartz, M. W. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.169722 · Cited by 364 · see citing works
Lumeng, C. N., Deyoung, S. M., & Saltiel, A. R. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00284.2006 · Cited by 359 · see citing works
Li, Y., Reddy, M. A., Miao, F., Shanmugam, N., Yee, J.-K., Hawkins, D., Ren, B., & Natarajan, R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802800200 · Cited by 353 · see citing works
Hotamisligil, G. S. (2005) · Diabetes · doi:10.2337/diabetes.54.suppl_2.s73 · Cited by 352 · see citing works
The 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
JNK1 and IKKβ: molecular links between obesity and metabolic dysfunction
Solinas, G., & Karin, M. (2010) · The FASEB Journal · doi:10.1096/fj.09-151340 · Cited by 347 · see citing works
Inflammation and the Metabolic Syndrome: The Tissue-Specific Functions of NF-κB
Catrysse, L., & van Loo, G. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.01.006 · Cited by 329 · see citing works
Obesity-related derangements in metabolic regulation
Muoio, D. M., & Newgard, C. B. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142512 · Cited by 345 · see citing works
Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise
Corcoran, M. P., Lamon-Fava, S., & Fielding, R. A. (2007) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/85.3.662 · Cited by 341 · see citing works
Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance
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., et al. (2010) · Diabetologia · doi:10.1007/s00125-010-1865-y · Cited by 334 · see citing works
The Role of the Immune System in Metabolic Health and Disease
Zmora, N., Bashiardes, S., Levy, M., & Elinav, E. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.02.006 · Cited by 323 · see citing works
Lee, Y.-S., Park, M.-S., Choung, J.-S., Kim, S.-S., Oh, H.-H., Choi, C.-S., Ha, S.-Y., Kang, Y., Kim, Y., & Jun, H.-S. (2012) · Diabetologia · doi:10.1007/s00125-012-2592-3 · Cited by 319 · see citing works
Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease
Anstee, Q. M., Mantovani, A., Tilg, H., & Targher, G. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0010-0 · Cited by 310 · see citing works
(n-3) Fatty Acids Alleviate Adipose Tissue Inflammation and Insulin Resistance: Mechanistic Insights
Kalupahana, N. S., Claycombe, K. J., & Moustaid-Moussa, N. (2011) · Advances in Nutrition · doi:10.3945/an.111.000505 · Cited by 305 · see citing works
Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance
Jia, L., Vianna, C. R., Fukuda, M., Berglund, E. D., Liu, C., Tao, C., Sun, K., Liu, T., Harper, M. J., Lee, C. E., et al. (2014) · Nature Communications · doi:10.1038/ncomms4878 · Cited by 294 · see citing works
Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62
Rodriguez, A., Durán, A., Selloum, M., Champy, M.-F., Diez-Guerra, F. J., Flores, J. M., Serrano, M., Auwerx, J., Diaz-Meco, M. T., & Moscat, J. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.011 · Cited by 290 · see citing works
PPARs, Obesity, and Inflammation
Stienstra, R., Duval, C., Müller, M., & Kersten, S. (2007) · PPAR Research · doi:10.1155/2007/95974 · Cited by 287 · see citing works
- Authors
- Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., & Shoelson, S. E.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- Shoelson, Steven E
- Venue
- Nature Medicine
- Published
- 2005-01-30
- Volume
- 11
- Issue
- 2
- Pages
- 183-190
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC1440292
- OpenAlex
- W1534360145
- Cited by
- 2,245
- References
- 49
- Citations by year
- 2026: 39 · 2025: 61 · 2024: 64 · 2023: 70 · 2022: 87 · 2021: 100 · 2020: 90 · 2019: 107 · 2018: 104 · 2017: 115 · 2016: 116 · 2015: 130 · 2014: 150 · 2013: 140 · 2012: 127
- FWCI
- 85.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-51729, R01 DK-45493, R01DK045943, R01DK051729, P30-DK36836, R37DK051729, P30DK036836)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- insulin resistance, NF-κB, IKKβ, liver inflammation, type 2 diabetes, high-fat diet, obesity, inflammatory cytokines, interleukin-6, TNF-α, IL-1β, salicylates, hepatic lipid accumulation, transgenic mice
- MeSH terms
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Dietary Fats, Female, Humans, Insulin, Insulin Resistance, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Salicylates, Signal Transduction, Interleukin-6, Cytokines, NF-kappa B, Protein Serine-Threonine Kinases, Hepatocytes, Carbohydrate Metabolism, Mice, Rats, I-kappa B Kinase
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
