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.
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Cover Image
Cover Image
The human oxoG DNA glycosylase hOGG1 senses and removes oxoG amid millions-fold excess of guanine, thereby counteracting the genotoxic effects of the major oxidative damage. In this issue Schmaltz and colleagues (pp. 2297–2309) determine a crystal structure of hOGG1 in complex with a fluorinated inhibitor using disulfide cross-linking technology. The cover image shows the interactions of oxoG lesion with the catalytic-site residues of hOGG1. The image is courtesy of Seongmin Lee.
Methylglyoxal induces multiple serine phosphorylation in insulin receptor substrate 1 via the TAK1–p38–mTORC1 signaling axis in adipocytes
Su-Ping Ng, Wataru Nomura, Haruya Takahashi, Kazuo Inoue, Teruo Kawada, Tsuyoshi Goto, Yoshiharu Inoue; Methylglyoxal induces multiple serine phosphorylation in insulin receptor substrate 1 via the TAK1–p38–mTORC1 signaling axis in adipocytes. Biochem J 11 November 2022; 479 (21): 2279–2296. doi: https://doi.org/10.1042/BCJ20220271
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