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Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase.
J Biol Chem. 1996 May 31; 271(22):13018-22.JB

Abstract

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.

Authors+Show Affiliations

Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8662983

Citation

Peraldi, P, et al. "Tumor Necrosis Factor (TNF)-alpha Inhibits Insulin Signaling Through Stimulation of the P55 TNF Receptor and Activation of Sphingomyelinase." The Journal of Biological Chemistry, vol. 271, no. 22, 1996, pp. 13018-22.
Peraldi P, Hotamisligil GS, Buurman WA, et al. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J Biol Chem. 1996;271(22):13018-22.
Peraldi, P., Hotamisligil, G. S., Buurman, W. A., White, M. F., & Spiegelman, B. M. (1996). Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. The Journal of Biological Chemistry, 271(22), 13018-22.
Peraldi P, et al. Tumor Necrosis Factor (TNF)-alpha Inhibits Insulin Signaling Through Stimulation of the P55 TNF Receptor and Activation of Sphingomyelinase. J Biol Chem. 1996 May 31;271(22):13018-22. PubMed PMID: 8662983.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. AU - Peraldi,P, AU - Hotamisligil,G S, AU - Buurman,W A, AU - White,M F, AU - Spiegelman,B M, PY - 1996/5/31/pubmed PY - 1996/5/31/medline PY - 1996/5/31/entrez SP - 13018 EP - 22 JF - The Journal of biological chemistry JO - J Biol Chem VL - 271 IS - 22 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/8662983/Tumor_necrosis_factor__TNF__alpha_inhibits_insulin_signaling_through_stimulation_of_the_p55_TNF_receptor_and_activation_of_sphingomyelinase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(18)41466-4 DB - PRIME DP - Unbound Medicine ER -