Neutralization of tumor necrosis factor-alpha reverses insulin resistance in skeletal muscle but not adipose tissue.
We examined the possible role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of insulin resistance in maturing male Sprague-Dawley rats. Rats were treated either with goat anti-murine TNF-alpha IgG (anti-TNF-alpha) 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-alpha 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-[(14)C]glucose during HUC. Anti-TNF-alpha 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-alpha did not alter the distribution of the 17-kDa and 26-kDa forms of TNF-alpha in either muscle or fat. However, anti-TNF-alpha treatment caused an approximately 50% reduction in the secretion of TNF-alpha bioactivity in vitro by explants of visceral and subcutaneous fat. We conclude that TNF-alpha neutralization reversed insulin resistance substantially in fast-twitch muscle and may have done so in other muscles, while having little effect in fat. TNF-alpha neutralization was accompanied by reduced TNF-alpha bioactivity without tissue depletion of TNF-alpha protein.
Borst
Stephen E
SE
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA. seborst@ufl.edu
Lee
Youngil
Y
Conover
Christine F
CF
Shek
Eugene W
EW
Bagby
Gregory J
GJ
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001786:Blood Glucose / Q000378:metabolism*; D001823:Body Composition; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D001786:Blood Glucose; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha