Journal
BIOCHEMICAL JOURNAL
Volume 479, Issue 21, Pages 2279-2296Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20220271
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Funding
- JSPS KAKENHI [20J23198, 19K05949, 21H02103, 21K19079]
- Lotte Shigemitsu Prize, Japan
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This study found that methylglyoxal (MG) activates mammalian target of rapamycin complex 1 (mTORC1) signaling through p38 mitogen-activated protein kinase in adipocytes. Activation of the TAK1-p38-mTORC1 signaling axis by MG leads to multiple serine phosphorylation of insulin receptor substrate-1 (IRS-1), which may contribute to insulin resistance.
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 rela-tionship 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-beta-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-alpha, 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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