Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha.
Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
Hotamisligil
G S
GS
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Budavari
A
A
Murray
D
D
Spiegelman
B M
BM
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000201:enzymology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000235:genetics; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D009500:Neutralization Tests; D009765:Obesity; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D007074:Immunoglobulin G; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin