title: Tumor necrosis factor alpha inhibits signaling from the insulin receptor.
abstract: Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: G S
authors.initials: GS
authors.lastname: Hotamisligil
authors.forename: D L
authors.initials: DL
authors.lastname: Murray
authors.forename: L N
authors.initials: LN
authors.lastname: Choy
authors.forename: B M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D007328:Insulin / Q000378:metabolism; D051379:Mice; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin