Neutralization of tumor necrosis factor-α reverses insulin resistance in skeletal muscle but not adipose tissue

Abstract

We examined the possible role of tumor necrosis factor-α (TNF-α) as a mediator of insulin resistance in maturing male Sprague-Dawley rats. Rats were treated either with goat anti-murine TNF-α IgG (anti-TNF-α) or goat nonimmune IgG (NI) for 7 days. Vascular catheters were implanted, and rats were fasted overnight before hyperinsulinemic euglycemic clamp (HUC) studies were performed. TNF-α neutralization increased the rate of glucose infusion required to maintain euglycemia by 68%. Insulin-stimulated glucose transport into individual tissues was measured after bolus administration of 2-deoxy-[14C]glucose during HUC. Anti-TNF-α administration increased glucose transport in muscles composed predominantly of fast-twitch fibers: white gastrocnemius muscle (68% increase) and tibialis anterior muscle (64% increase). There were nonsignificant trends for increased glucose transport in the slow-twitch soleus muscle and in the mixed-fiber red gastrocnemius muscle. Glucose transport was unchanged in visceral and subcutaneous fat. Anti-TNF treatment did not alter body weight, muscle mass, or fat mass. Anti-TNF-α did not alter the distribution of the 17-kDa and 26-kDa forms of TNF-α in either muscle or fat. However, anti-TNF-α treatment caused an ∼50% reduction in the secretion of TNF-α bioactivity in vitro by explants of visceral and subcutaneous fat. We conclude that TNF-α neutralization reversed insulin resistance substantially in fast-twitch muscle and may have done so in other muscles, while having little effect in fat. TNF-α neutralization was accompanied by reduced TNF-α bioactivity without tissue depletion of TNF-α protein.