Methylglyoxal induces multiple serine phosphorylation in insulin receptor substrate 1 via the TAK1-p38-mTORC1 signaling axis in adipocytes
Methylglyoxal induces multiple serine phosphorylation in insulin receptor substrate 1 via the TAK1-p38-mTORC1 signaling axis in adipocytes
复制标题
甲基乙二醛通过脂肪细胞中的 TAK1-p38-mTORC1 信号轴诱导胰岛素受体底物 1 中的多重丝氨酸磷酸化
DOI：
10.1042/bcj20220271
复制
发表时间：
2022
影响因子：
4.1
通讯作者：
Inoue Yoshiharu
中科院分区：
文献类型：
--
作者：
Ng Su-Ping;Nomura Wataru;Takahashi Haruya;Inoue Kazuo;Kawada Teruo;Goto Tsuyoshi;Inoue Yoshiharu
已知代谢过程中产生的某些代谢中间产物调节广泛的细胞过程。丙酮醛（MG）是糖酵解产生的天然代谢产物，可引起葡萄糖耐受不良、胰岛素抵抗和糖尿病并发症，对全身代谢产生负面影响。MG作为启动信号转导的信号分子发挥功能作用。然而，MG诱导的信号转导激活及其对代谢的负面影响之间的具体关系仍不清楚。在此，我们发现MG通过脂肪细胞中的p38丝裂原活化蛋白激酶激活哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）信号传导，并且MG处理后需要转化生长因子-β-活化激酶1（TAK 1）来激活p38-mTORC 1信号传导。我们还发现，MG增加了胰岛素受体底物（IRS）-1的丝氨酸残基的磷酸化水平，这是参与其负调控，从而减弱胰岛素刺激的IRS-1的酪氨酸磷酸化。MG对胰岛素刺激的IRS-1酪氨酸磷酸化的负面影响是由于MG诱导的TAK 1-p38-mTORC 1信号轴的激活而产生的。TAK 1-p38-mTORC 1信号轴参与IRS-1多丝氨酸磷酸化的诱导并非MG所独有，因为促炎细胞因子肿瘤坏死因子-α也激活了相同的信号轴。因此，我们的研究结果表明，MG诱导的TAK 1-p38-mTORC 1信号轴的激活导致IRS-1上的多个丝氨酸磷酸化，可能有助于胰岛素抵抗。
Certain metabolic intermediates produced during metabolism are known to regulate a wide range of cellular processes. Methylglyoxal (MG), a natural metabolite derived from glycolysis, has been shown to negatively influence systemic metabolism by inducing glucose intolerance, insulin resistance, and diabetic complications. MG plays a functional role as a signaling molecule that initiates signal transduction. However, the specific relationship between MG-induced activation of signal transduction and its negative effects on metabolism remains unclear. Here, we found that MG activated mammalian target of rapamycin complex 1 (mTORC1) signaling via p38 mitogen-activated protein kinase in adipocytes, and that the transforming growth factor-β-activated kinase 1 (TAK1) is needed to activate p38–mTORC1 signaling following treatment with MG. We also found that MG increased the phosphorylation levels of serine residues in insulin receptor substrate (IRS)-1, which is involved in its negative regulation, thereby attenuating insulin-stimulated tyrosine phosphorylation in IRS-1. The negative effect of MG on insulin-stimulated IRS-1 tyrosine phosphorylation was exerted due to the MG-induced activation of the TAK1–p38–mTORC1 signaling axis. The involvement of the TAK1–p38–mTORC1 signaling axis in the induction of IRS-1 multiple serine phosphorylation was not unique to MG, as the proinflammatory cytokine, tumor necrosis factor-α, also activated the same signaling axis. Therefore, our findings suggest that MG-induced activation of the TAK1–p38–mTORC1 signaling axis caused multiple serine phosphorylation on IRS-1, potentially contributing to insulin resistance.