Tumor Necrosis Factor (TNF)-α Inhibits Insulin Signaling through Stimulation of the p55 TNF Receptor and Activation of Sphingomyelinase
Open accessAbstract
Tumor necrosis factor (TNF)-alpha plays a central role in the state of insulin resistance associated with obesity. It has previously been shown that one important mechanism by which TNF-alpha interferes with insulin signaling is through the serine phosphorylation of insulin receptor substrate-1 (IRS-1), which can then function as an inhibitor of the tyrosine kinase activity of the insulin receptor (IR). However, the receptors and the signaling pathway used by TNF-alpha that mediate the inhibition of IR activity are unknown. We show here that human TNF-alpha, which binds only to the murine p55 TNF receptor (TNFR), is as effective at inhibiting insulin-dependent tyrosine phosphorylation of IR and IRS-1 in adipocytes and myeloid 32D cells as murine TNF-alpha, which binds to both p55 TNFR and p75 TNFR. Likewise, antibodies that are specific agonists for p55 TNFR or p75 TNFR demonstrate that stimulation of p55 TNFR is sufficient to inhibit insulin signaling, though a small effect can also be seen with antibodies to p75 TNFR. Exogenous sphingomyelinase and ceramides, known to be formed by activation of p55 TNFR, inhibit IR and IRS-1 tyrosine phosphorylation and convert IRS-1 into an inhibitor of IR tyrosine kinase in vitro. Myeloid 32D cells expressing IR and IRS-1 are sensitive to this inhibition, but cells expressing IR and IRS-2 are resistant, pointing to an important difference in the biological function between IRS-1 and IRS-2. These data strongly suggest that TNF-alpha inhibits insulin signaling via stimulation of p55 TNFR and sphingomyelinase activity, which results in the production of an inhibitory form of IRS-1.
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?
TNF-α downregulates GLUT4 and inhibits insulin-dependent tyrosine phosphorylation of the insulin receptor and IRS-1 through ceramide production.
“It downregulates the major insulin-responsive glucose transporter GLUT4 and inhibits insulin-dependent tyrosine phosphorylation of the insulin receptor and IRS-1 through ceramide production (70,71).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [71]
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
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
Self-citationHotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L., & Spiegelman, B. M. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117936 · Cited by 3,543 · see citing works
Self-citationHotamisligil, G. S., Peraldi, P., Budavari, A., Ellis, R., White, M. F., & Spiegelman, B. M. (1996) · Science · doi:10.1126/science.271.5249.665 · Cited by 2,630 · see citing works
Self-citationThe TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation
Hsu, H., Xiong, J., & Goeddel, D. V. (1995) · Cell · doi:10.1016/0092-8674(95)90070-5 · Cited by 2,024 · see citing works
White, M. F., & Kahn, C. R. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42297-6 · Cited by 1,723 · see citing works
Self-citationPfeffer, K., Matsuyama, T., Kündig, T. M., Wakeham, A., Kishihara, K., Shahinian, A., Wiegmann, K., Ohashi, P. S., Krönke, M., & Mak, T. W. (1993) · Cell · doi:10.1016/0092-8674(93)90134-c · Cited by 1,677 · see citing works
Kern, P. A., Saghizadeh, M., Ong, J. M., Bosch, R. J., Deem, R., & Simsolo, R. B. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117899 · Cited by 1,305 · see citing works
Tumor Necrosis Factor α: A Key Component of the Obesity-Diabetes Link
Hotamışlıgil, G. S., & Spiegelman, B. M. (1994) · Diabetes · doi:10.2337/diab.43.11.1271 · Cited by 1,287 · see citing works
Self-citationRothe, J., Lesslauer, W., Loetscher, H., Lang, Y., Koebel, P., Köntgen, F., Althage, A., Zinkernagel, R. M., Steinmetz, M., & Bluethmann, H. (1993) · Nature · doi:10.1038/364798a0 · Cited by 1,246 · see citing works
Tumor necrosis factor alpha inhibits signaling from the insulin receptor.
Hotamışlıgil, G. S., Murray, D. L., Choy, L., & Spiegelman, B. M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.11.4854 · Cited by 1,206 · see citing works
Self-citationRothe, M., Wong, S. C., Henzel, W. J., & Goeddel, D. V. (1994) · Cell · doi:10.1016/0092-8674(94)90532-0 · Cited by 1,054 · see citing works
Mosialos, G., Birkenbacht, M., Yalamanchill, R., Arsdale, T. V., Ware, C. F., & Kleff, E. (1995) · Cell · doi:10.1016/0092-8674(95)90489-1 · Cited by 980 · see citing works
Stanger, B. Z., Leder, P., Lee, T.-H., Kim, E., & Seed, B. (1995) · Cell · doi:10.1016/0092-8674(95)90072-1 · Cited by 969 · see citing works
The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling
Kolesnick, R. N. (1994) · Cell · doi:10.1016/0092-8674(94)90147-3 · Cited by 932 · see citing works
Role of IRS-2 in insulin and cytokine signalling
Sun, X. J., Wang, L.-M., Zhang, Y., Yenush, L., Myers, M. G., Glasheen, E. M., Lane, W. S., Pierce, J. H., & White, M. F. (1995) · Nature · doi:10.1038/377173a0 · Cited by 847 · see citing works
Self-citationHotamisligil, G. S., Budavari, A., Murray, D., & Spiegelman, B. M. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117495 · Cited by 819 · see citing works
Self-citationTwo tumour necrosis factor receptors: structure and function
Vandenabeele, P., Declercq, W., Beyaert, R., & Fiers, W. (1995) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)89088-1 · Cited by 799 · see citing works
The expression of TNF alpha by human muscle. Relationship to insulin resistance.
Saghizadeh, M., Ong, J. M., Garvey, W. T., Henry, R. R., & Kern, P. A. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118504 · Cited by 717 · see citing works
Erickson, S. L., de Sauvage, F. J., Kikly, K. K., Carver-Moore, K., Pitts-Meek, S., Gillett, N. A., Sheehan, K. C. F., Schreiber, R. D., Goeddel, D. V., & Moore, M. W. (1994) · Nature · doi:10.1038/372560a0 · Cited by 587 · see citing works
Lewis, M., Tartaglia, L. A., Lee, A. L., Bennett, G. L., Rice, G. C., Wong, G. H., Chen, E. Y., & Goeddel, D. V. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.7.2830 · Cited by 561 · see citing works
Feinstein, 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
Lozano, J., Berra, E., Municio, M. M., Díaz-Meco, M. T., Dominguez, I. M., Sanz, L., & Moscat, J. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32152-x · Cited by 465 · see citing works
Tumor Necrosis Factor α-induced Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)
Kanety, H., Feinstein, R., Papa, M. Z., Hemi, R., & Karasik, A. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.40.23780 · Cited by 435 · see citing works
IRS-1: Essential for Insulin- and IL-4-Stimulated Mitogenesis in Hematopoietic Cells
Wang, L.-M., Myers, M. G., Sun, X., Aaronson, S. A., White, M. F., & Pierce, J. H. (1993) · Science · doi:10.1126/science.8372354 · Cited by 395 · see citing works
Self-citationTumor necrosis factor receptor-mediated signaling pathways.
Heller, R. A., & Krönke, M. (1994) · The Journal of Cell Biology · doi:10.1083/jcb.126.1.5 · Cited by 392 · see citing works
Hofmann, C. A., Lorenz, K., Braithwaite, S. S., Colca, J. R., Palazuk, B. J., Hotamışlıgil, G. S., & Spiegelman, B. M. (1994) · Endocrinology · doi:10.1210/endo.134.1.8275942 · Cited by 387 · see citing works
Self-citationCeramide stimulates a cytosolic protein phosphatase.
Dobrowsky, R., & Hannun, Y. A. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)42727-5 · Cited by 376 · see citing works
Phosphorylation of Raf by ceramide-activated protein kinase
Yao, B., Zhang, Y., Delikat, S. E., Mathias, S., Basu, S., & Kolesnick, R. (1995) · Nature · doi:10.1038/378307a0 · Cited by 327 · see citing works
Saad, M. J. A., Araki, E., Miralpeix, M., Rothenberg, P., White, M. F., & Kahn, C. R. (1992) · Journal of Clinical Investigation · doi:10.1172/jci116060 · Cited by 323 · see citing works
Self-citationSong, H. Y., Dunbar, J. D., Zhang, Y. X., Guo, D., & Donner, D. B. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.8.3574 · Cited by 266 · see citing works
Patti, M., Sun, X., Bruening, J., Araki, E., Lipes, M. A., White, M. F., & Kahn, C. R. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.42.24670 · Cited by 238 · see citing works
Self-citationLiu, J., Mathias, S., Yang, Z., et al. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42045-x · Cited by 203 · see citing works
Wang, L. M., Keegan, A. D., Li, W., Lienhard, G. E., Pacini, S., Gutkind, J. S., Myers, M. G., Sun, X., White, M. F., & Aaronson, S. A. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.9.4032 · Cited by 168 · see citing works
Self-citationde Herreros, A. G., & Birnbaum, M. J. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)47209-8 · Cited by 144 · see citing works
Paleolog, E. M., Delasalle, S., Buurman, W. A., & Feldmann, M. (1994) · Blood · doi:10.1182/blood.v84.8.2578.2578 · Cited by 109 · see citing works
Self-citationBelka, C., Wiegmann, K., Adam, D., Holland, R., Neuloh, M., Herrmann, F., Krönke, M., & Brach, M. A. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07099.x · Cited by 95 · see citing works
Characterization of Insulin Resistance and NIDDM in Transgenic Mice With Reduced Brown Fat
Hamann, A., Benecke, H., Marchand-Brustel, Y. L., Susulic, V. S., Lowell, B. B., & Flier, J. S. (1995) · Diabetes · doi:10.2337/diab.44.11.1266 · Cited by 89 · see citing works
Thies, R. S., Molina, J. M., Ciaraldi, T. P., Freidenberg, G. R., & Olefsky, J. M. (1990) · Diabetes · doi:10.2337/diab.39.2.250 · Cited by 82 · see citing works
Flagged first, then by citations
Research works printed but not linked: 6
- Olefsky, J., and Molina, J. (1990) in Diabetes Mellitus (Rifkin, H., and Porte, D. J., eds) pp. 121-153, Elsevier Science Publishing Co., Inc., New York
- Bennet, P. (1990) in Diabetes Mellitus (Rifkin, H., and Porte, J. D., eds) pp. 357-377, Elsevier Science Publishing Co., Inc., New York
- Hotamisligil, G. S., Murray, D. L., Choy, L. N., and Spiegelman, B. M. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 4854 -4858
- Wang, L. M., Keegan, A. D., Li, W., Lienhard, G. E., Pacini, S., Gutkind, J. S., Myers, M. G., Sun, X. J., White, M. F., Aaronson, S. A., Paul, W. E., and Pierce, J. H. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 4032-4036
- Lewis, M., Tartaglia, L., Lee, A., Bennett, G., Rice, G., Wong, G. H. W., Chen, E., and Goeddel, D. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 2830 -2834
- Sheperd, P., and Khan, B. (1993) in Insulin Resistance (Moller, D. E., ed) pp. 253-300, John Wiley & Sons, Inc., New York
Cited by
Sorted by citations
Adipose Tissue as an Endocrine Organ
Kershaw, E. E., & Flier, J. S. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0395 · Cited by 5,522 · see citing works
The anti-inflammatory effect of exercise
Petersen, A. M. W., & Pedersen, B. K. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00164.2004 · Cited by 3,100 · see citing works
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028 · see citing works
Aguirre, V., Uchida, T., Yenush, L., Davis, R., & White, M. F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.9047 · Cited by 1,487 · see citing works
Self-citationAguirre, V., Werner, E. D., Giraud, J., Lee, Y. H., Shoelson, S. E., & White, M. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m101521200 · Cited by 1,010 · see citing works
Self-citationCellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes
Barbour, L. A., McCurdy, C. E., Hernandez, T. L., Kirwan, J. P., Catalano, P. M., & Friedman, J. E. (2007) · Diabetes Care · doi:10.2337/dc07-s202 · Cited by 811 · see citing works
The role of TNFα and TNF receptors in obesity and insulin resistance
Hotamisligil, G. S. (1999) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.1999.00490.x · Cited by 780 · see citing works
The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.
Crewe, C., An, Y. A., & Scherer, P. E. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88883 · Cited by 732 · 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
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
Ueki, K., Kondo, T., & Kahn, C. R. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.12.5434-5446.2004 · Cited by 686 · see citing works
Stephens, J. M., Lee, J., & Pilch, P. F. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.2.971 · Cited by 553 · see citing works
Summers, S. A., Garza, L. A., Zhou, H., & Birnbaum, M. J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.9.5457 · Cited by 475 · see citing works
Regulation of Insulin Action by Ceramide
Stratford, S., Hoehn, K. L., Liu, F., & Summers, S. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406499200 · Cited by 410 · see citing works
Ganglioside GM3 Participates in the Pathological Conditions of Insulin Resistance
Tagami, S., Inokuchi, J.-I., Kabayama, K., Yoshimura, H., Kitamura, F., Uemura, S., Ogawa, C., Ishii, A., Saito, M., Ohtsuka, Y., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m103705200 · Cited by 355 · see citing works
S-Nitrosation of the Insulin Receptor, Insulin Receptor Substrate 1, and Protein Kinase B/Akt
Carvalho-Filho, M. A., Ueno, M., Hirabara, S. M., Seabra, A. B., Carvalheira, J. B. C., de Oliveira, M. G., Velloso, L. A., Curi, R., & Saad, M. J. A. (2005) · Diabetes · doi:10.2337/diabetes.54.4.959 · Cited by 277 · see citing works
Alzheimer's disease and type 2 diabetes: a critical assessment of the shared pathological traits
Chatterjee, S., & Mudher, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00383 · Cited by 270 · see citing works
Kabayama, K. (2004) · Glycobiology · doi:10.1093/glycob/cwh135 · Cited by 155 · see citing works
Obesity: A neuroimmunometabolic perspective
Larabee, C. M., Neely, O. C., & Domingos, A. I. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0283-6 · Cited by 123 · see citing works
Mazhar, M., Zhu, Y., & Qin, L. (2023) · Foods · doi:10.3390/foods12051023 · Cited by 119 · see citing works
Rydén, M., & Arner, P. (2007) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2007.01854.x · Cited by 118 · see citing works
Adipose tissue as an endocrine organ
Prins, J. B. (2002) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1053/beem.2002.0222 · Cited by 121 · see citing works
Carvalho-Filho, M. A., Ueno, M., Carvalheira, J. B. C., Velloso, L. A., & Saad, M. J. A. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00422.2005 · Cited by 84 · see citing works
Adipokines in healthy skeletal muscle and metabolic disease
Coles, C. A. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-27511-6_6 · Cited by 39 · see citing works
- Authors
- Peraldi, P., Hotamisligil, G. S., Buurman, W. A., White, M. F., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Spiegelman, Bruce M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-05
- Volume
- 271
- Issue
- 22
- Pages
- 13018-13022
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1971762417
- Cited by
- 412
- References
- 38
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 9 · 2023: 10 · 2022: 9 · 2021: 15 · 2020: 14 · 2019: 13 · 2018: 17 · 2017: 10 · 2016: 14 · 2015: 17 · 2014: 13 · 2013: 9 · 2012: 19
- FWCI
- 19.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- TNF-α, insulin signaling, TNF receptor p55, TNF receptor 2, sphingomyelinase, ceramide, insulin receptor tyrosine phosphorylation, IRS-1, insulin receptor substrate 2, insulin resistance, obesity, adipocytes
- MeSH terms
- Animals, Cell Line, Ceramides, Enzyme Activation, Humans, Insulin, Phosphoproteins, Phosphorylation, Receptor, Insulin, Sphingomyelin Phosphodiesterase, Tumor Necrosis Factor-alpha, Tyrosine, Signal Transduction, Antigens, CD, 3T3 Cells, Adipocytes, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Mice, Insulin Receptor Substrate Proteins
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
