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.
Key words
Obesity - type 2 diabetes - cytokines - insulin action - adipocyte
