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

作者：Ishizuka Ken; Usui Isao^*; Kanatani Yukiko; Bukhari Agussalim; He Jianying; Fujisaka Shiho; Yamazaki Yu; Suzuki Hikari; Hiratani Kazuyuki; Ishiki Manabu; Iwata Minoru; Urakaze Masaharu; Haruta Tetsuro; Kobayashi Masashi

来源：Endocrinology, 2007, 148(6): 2994-3003.

DOI：10.1210/en.2006-1702

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 TNF alpha-induced insulin resistance in 3T3- L1 adipocytes. TNF alpha transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNF alpha 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 TNF alpha. TNF alpha 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 TNF alpha treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNF alpha. 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 TNF alpha 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 TNF alpha may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.

• 出版日期2007-6