Effect of tumor necrosis factor-alpha on insulin signal transduction in rat adipocytes: relation to PKCbeta and zeta translocation.
Although much evidence has been accumulated suggesting that tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance, the precise mechanism involved is still unclear. Recently, it has been reported that insulin-induced glucose uptake is mediated by activation of second messengers such as insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and diacylglycerol (DG)-protein kinase C (PKC). We have examined the effect of TNF-alpha on insulin-induced glucose uptake and activations of tyrosine kinase, IRS-1, PI3K and PKC in rat adipocytes. Pretreatment with 0.1-100 nM TNF-alpha for 60 min resulted in a significant decrease in 10 nM insulin- or 1 microM 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced [3H]2-deoxyglucose uptake without affecting basal glucose uptake. 10 nM insulin-stimulated activation of tyrosine kinase, IRS-1 and PI3K was suppressed by preincubation with 0.1-10 nM TNF-alpha for 60 min. 10 nM TNF-alpha pretreatment also suppressed 10 nM insulin- and 1 microM TPA-induced increases in membrane-associated PKCbeta and PKCzeta. Furthermore, 10 nM TNF-alpha, by itself, altered PKCbeta translocation from the membrane to cytosol. These results suggest that TNF-alpha inhibits insulin-stimulated activation of both the tyrosine kinase-IRS-1-PI3K-PKCzeta pathway and DG-PKC pathway. Finally, TNF-alpha contributes to insulin resistance in rat adipocytes.
Miura
A
A
The Third Department of Internal Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan.
Ishizuka
T
T
Kanoh
Y
Y
Ishizawa
M
M
Itaya
S
S
Kimura
M
M
Kajita
K
K
Yasuda
K
K
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000099221:Protein Kinase C zeta
D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes; D010750:Phosphoproteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta; C526296:Irs1 protein, rat