Mechanisms of TNF-α-induced insulin resistance

 

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Summary

There is now substantial evidence linking TNF-α to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-α and insulin resistance using knockout mice deficient for either TNF-α or one or both of its receptors, p55 and p75.

In studies of TNF-α-deficient knockout mice with diet-induced obesity, obese TNF-α knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-α wild-type animals. This finding suggests that deletion of TNF-α leads to increased insulin sensitivity, ie decreased insulin resistance.

In studies using genetically obese ob I ob mice, TNF-α receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout.

animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-α's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75.

How TNF-α-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-α wild-type and knockout mice, we found no convincing evidence that TNF-α mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-α knockout mice, suggesting that insulin receptor signalling is an important target for TNF-α. Other possible mediators of TNF-α-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.