Adipose tumor necrosis factor-alpha is reduced during onset of insulin resistance in Sprague-Dawley rats

Overexpression of mRNA for tumor necrosis factor-alpha (TNF-alpha) has been observed in adipose tissue in several rodent models of insulin resistance. The purpose of the present study was to examine the expression of TNF-alpha protein during the onset of insulin resistance in maturing Sprague-Dawley (S-D) rats. Compared to 2 months, rats aged 5 and 12 months were glucose intolerant and fasting glucose was elevated at 12 months (p < 0.05). Compared to 2 months, insulin concentrations following glucose loading were elevated at 5 months (p < 0.05) and also at 12 months, but to a lesser degree. In isolated strips of soleus muscle, insulin-stimulated glucose transport was reduced by 38% and 59% between 2 and 5 months and between 2 and 12 months, respectively (p < 0.05), with no changes in basal transport. Insulin resistance was associated with decreased content of TNF-alpha protein in visceral and subcutaneous fat. TNF-alpha protein content was also decreased in tibialis anterior muscle, but was unchanged in soleus and red gastrocnemius muscles. Liver was the only tissue examined that showed an increase in TNF-alpha protein content. In vitro secretion of TNF-alpha protein was markedly reduced in explants of visceral and subcutaneous fat from mature, insulin-resistant animals, but TNF-alpha bioactivity in subcutaneous fat was maintained with age. These results indicate that the onset of insulin resistance in mature S-D rats is associated with reduced adipose expression of TNF-alpha. Our findings do not support the adipose-endocrine model of TNF-alpha in insulin resistance. Our findings do support a paracrine role for TNF-alpha or for a reduction in endogenous TNF-alpha inhibitors in insulin resistance.