The effect of tumor necrosis factor-alpha on tissue specificity and selectivity to insulin signaling.
Recent studies have indicated that tumor necrosis factor (TNF)-alpha plays a significant role in insulin resistance. It has been proposed that selective impairment of insulin signaling in glucose metabolism is related to the development of atherosclerosis, although the mechanisms are not clear. The aim of this study was to elucidate the effect of TNF-alpha on tissue specificity and selectivity to insulin signaling. L6 myotubes and rat aortic vascular smooth muscle cells (VSMC) were cultured. Cells were stimulated with insulin pretreated with or without TNF-alpha. The protein extracts were used for electrophoresis and immunoblotting studies to examine phosphorylation of insulin receptor (IR)-beta, insulin receptor substrate (IRS)-1 and extracellular signal-regulated kinase (ERK). IR-beta phosphorylation was not affected by TNF-alpha in L6 or in VSMC. TNF-alpha significantly (p<0.05) inhibited IRS-1 phosphorylation by insulin but had no effect on ERK in L6. TNF-alpha had no effect on either IRS-1 phosphorylation or ERK in VSMC. Insulin induced ERK phosphorylation in a dose-dependent manner in VSMC. These results suggests that TNF-alpha plays a significant role in the tissue specificity and signal selectivity of insulin resistance. The pathway related to glucose metabolism is selectively impaired by TNF-alpha in skeletal muscle, and this impairment may induce compensatory hyperinsulinemia, which in turn would stimulate the pathway related to the cell proliferation in vascular tissues and possibly enhance the progression of atherosclerosis.
Yamaguchi
Koichi
K
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. ykouichi@sapmed.ac.jp
Higashiura
Katsuhiro
K
Ura
Nobuyuki
N
Murakami
Hideyuki
H
Hyakukoku
Masaya
M
Furuhashi
Masato
M
Shimamoto
Kazuaki
K
D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D012680:Sensitivity and Specificity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D000963:Antimetabolites; D000970:Antineoplastic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D003847:Deoxyglucose; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases