Ikubo Mariko, Wada Tsutomu, Fukui Kazuhito, Ishiki Manabu, Ishihara Hajime, Asano Tomoichiro, Tsuneki Hiroshi, Sasaoka Toshiyasu
Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Am J Physiol Endocrinol Metab. 2009 Jan;296(1):E157-64. doi: 10.1152/ajpendo.90581.2008. Epub 2008 Nov 11.
TNF-alpha is a major contributor to the pathogenesis of insulin resistance associated with obesity and inflammation by serine phosphorylating and degrading insulin receptor substrate-1. Presently, we further found that pretreatment with TNF-alpha inhibited insulin-induced phosphorylation of Akt2 greater than Akt1. Since lipid phosphatases SH2-containing inositol 5'-phoshatase 2 (SHIP2) and phosphatase and tensin homologs deleted on chromosome 10 (PTEN) are negative regulators of insulin's metabolic signaling at the step downstream of phosphatidylinositol 3-kinase, we investigated the Akt isoform-specific properties of these phosphatases in the negative regulation after short- and long-term insulin treatment and examined the influence of inhibition on the amelioration of insulin resistance caused by TNF-alpha in 3T3-L1 adipocytes. Adenovirus-mediated overexpression of WT-SHIP2 decreased the phosphorylation of Akt2 greater than Akt1 after insulin stimulation up to 15 min. Expression of a dominant-negative DeltaIP-SHIP2 enhanced the phosphorylation of Akt2 up to 120 min. On the other hand, overexpression of WT-PTEN inhibited the phosphorylation of both Akt1 and Akt2 after short- but not long-term insulin treatment. The expression of DeltaIP-PTEN enhanced the phosphorylation of Akt1 at 120 min and that of Akt2 at 2 min. Interestingly, the expression of DeltaIP-SHIP2, but not DeltaIP-PTEN, protected against the TNF-alpha inhibition of insulin-induced phosphorylation of Akt2, GSK3, and AS160, whereas both improved the TNF-alpha inhibition of insulin-induced 2-deoxyglucose uptake. The results indicate that these lipid phosphatases possess different characteristics according to the time and preference of Akt isoform-dependent signaling in the negative regulation of the metabolic actions of insulin, whereas both inhibitions are effective in the amelioration of insulin resistance caused by TNF-alpha.
肿瘤坏死因子-α（TNF-α）通过丝氨酸磷酸化和降解胰岛素受体底物-1，在与肥胖和炎症相关的胰岛素抵抗发病机制中起主要作用。目前，我们进一步发现，用TNF-α预处理对胰岛素诱导的Akt2磷酸化的抑制作用大于Akt1。由于含SH2结构域的肌醇5'-磷酸酶2（SHIP2）和10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）等脂质磷酸酶是磷脂酰肌醇3激酶下游步骤中胰岛素代谢信号的负调节因子，我们研究了这些磷酸酶在短期和长期胰岛素处理后的负调节中Akt亚型特异性特性，并检测了抑制作用对3T3-L1脂肪细胞中TNF-α所致胰岛素抵抗改善的影响。腺病毒介导的野生型SHIP2过表达在胰岛素刺激后15分钟内对Akt2磷酸化的降低作用大于Akt1。显性负性DeltaIP-SHIP2的表达在长达120分钟内增强了Akt2的磷酸化。另一方面，野生型PTEN的过表达在短期而非长期胰岛素处理后抑制了Akt1和Akt2的磷酸化。DeltaIP-PTEN的表达在120分钟时增强了Akt1的磷酸化，在2分钟时增强了Akt2的磷酸化。有趣的是，DeltaIP-SHIP2而非DeltaIP-PTEN的表达可防止TNF-α对胰岛素诱导的Akt2、糖原合成酶激酶3（GSK3）和AS160磷酸化的抑制作用，而两者均改善了TNF-α对胰岛素诱导的2-脱氧葡萄糖摄取的抑制作用。结果表明，这些脂质磷酸酶在胰岛素代谢作用的负调节中，根据Akt亚型依赖性信号传导的时间和偏好具有不同特性，而两种抑制作用均对TNF-α所致胰岛素抵抗的改善有效。
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