Interleukin-1 (cid:1) -Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression
Interleukin-1 (cid:1) -Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression
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炎症与肥胖和胰岛素抵抗有关，肥胖时脂肪组织产生的促炎细胞因子可改变胰岛素信号和作用，最近的研究表明IL-1（cid：1）水平与代谢综合征和2型糖尿病之间存在关系。然而，IL-1（cid：1）改变胰岛素信号传导和作用的能力仍有待探索。我们发现IL-1（cid：1）可轻微增加3 T3-L1脂肪细胞中Glut 1的转位和基础葡萄糖摄取，重要的是，我们发现长期IL-1（cid：1）处理可降低胰岛素诱导的葡萄糖摄取，而急性处理无此作用，慢性IL-1（cid：1）处理可轻微降低Glut 4的表达，并显著抑制其对胰岛素应答的质膜转位。这种抑制作用是由于3 T3-L1和人脂肪细胞中胰岛素受体底物（IRS）-1而不是IRS-2表达量的减少。IRS-1含量的降低导致其酪氨酸磷酸化水平降低，胰岛素诱导的蛋白激酶B活化和AS 160磷酸化水平改变。ERK的药理作用可完全抑制IL-1（cid：1）诱导的IRS-1 mRNA的下调。此外，IRS-1蛋白表达和胰岛素诱导的蛋白激酶B激活，AS 160磷酸化，和Glut 4易位与ERK抑制剂治疗后部分恢复。这些结果表明，IL-1（cid：1）通过ERK依赖性机制在转录水平降低IRS-1表达，并在转录后水平独立于ERK激活。通过靶向IRS-1，IL-1（cid：1）能够损害胰岛素信号传导和作用，并且因此可以与其他细胞因子一起参与脂肪细胞中胰岛素抵抗的发展。（内分泌学148：241-251，2007）
Inflammation is associated with obesity and insulin resis-tance.Proinflammatorycytokinesproducedbyadiposetissueinobesitycouldalterinsulinsignalingandaction.RecentstudieshaveshownarelationshipbetweenIL-1 (cid:1) level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1 (cid:1) to alter insulin signaling and action remains to be explored. We demonstrated that IL-1 (cid:1) slightly increased Glut 1translocationandbasalglucoseuptakein3T3-L1adipocytes.Importantly,wefoundthatprolongedIL-1 (cid:1) treatment reduced the insulin-induced glucose uptake, whereas an acute treatmenthadnoeffect.ChronictreatmentwithIL-1 (cid:1) slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphoryla- tion and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological in- hibition of ERK totally inhibited IL-1 (cid:1) -induced down-regula-tion of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1 (cid:1) reduces IRS-1 expression at a transcrip- tional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activa- tion. By targeting IRS-1, IL-1 (cid:1) is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes. ( Endocrinology 148: 241–251, 2007)