title: Chronic tumor necrosis factor-alpha treatment causes insulin resistance via insulin receptor substrate-1 serine phosphorylation and suppressor of cytokine signaling-3 induction in 3T3-L1 adipocytes.
abstract: Serine phosphorylation of insulin receptor substrate (IRS)-1 and the induction of suppressor of cytokine signaling 3 (SOCS3) is recently well documented as the mechanisms for the insulin resistance. However, the relationship between these two mechanisms is not fully understood. In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFalpha-induced insulin resistance in 3T3-L1 adipocytes. TNFalpha transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNFalpha treatment longer than 4 h. These results suggest that serine phosphorylation of IRS-1 alone is not the major mechanism for the inhibited insulin signaling by TNFalpha. TNFalpha stimulation longer than 4 h enhanced the expression of SOCS3 and signal transducer and activator of transcription-3 phosphorylation, concomitantly with the production of IL-6. Anti-IL-6 neutralizing antibody ameliorated suppressed insulin signaling by 24 h TNFalpha treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription-3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNFalpha. However, low-level expression of SOCS3 by IL-6 or adenovirus vector did not affect insulin-stimulated IRS-1 tyrosine phosphorylation. Interestingly, when IRS-1 serine phosphorylation was enhanced by TNFalpha or anisomycin in the presence of low-level SOCS3, IRS-1 degradation was remarkably enhanced. Taken together, both IRS-1 serine phosphorylation and SOCS3 induction are necessary, but one of the pair is not sufficient for the inhibited insulin signaling. Chronic TNFalpha may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.
authors: The First Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Ken
authors: K
authors: Ishizuka
authors: Isao
authors: I
authors: Usui
authors: Yukiko
authors: Y
authors: Kanatani
authors: Agussalim
authors: A
authors: Bukhari
authors: Jianying
authors: J
authors: He
authors: Shiho
authors: S
authors: Fujisaka
authors: Yu
authors: Y
authors: Yamazaki
authors: Hikari
authors: H
authors: Suzuki
authors: Kazuyuki
authors: K
authors: Hiratani
authors: Manabu
authors: M
authors: Ishiki
authors: Minoru
authors: M
authors: Iwata
authors: Masaharu
authors: M
authors: Urakaze
authors: Tetsuro
authors: T
authors: Haruta
authors: Masashi
authors: M
authors: Kobayashi
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013995:Time; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases