Methylglyoxal induces multiple serine phosphorylation in insulin receptor substrate 1 via the TAK1-p38-mTORC1 signaling axis in adipocytes

Biochem J. 2022 Nov 11;479(21):2279-2296. doi: 10.1042/BCJ20220271.

Abstract

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.

Keywords: TAK1; adipocytes; insulin signalling; mTOR; methylglyoxal; signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance* / physiology
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Phosphoproteins / metabolism
  • Pyruvaldehyde* / metabolism
  • Pyruvaldehyde* / pharmacology
  • Serine / metabolism
  • Signal Transduction / physiology
  • Tyrosine / metabolism

Substances

  • Insulin Receptor Substrate Proteins
  • Pyruvaldehyde
  • Serine
  • Insulin
  • Mechanistic Target of Rapamycin Complex 1
  • Tyrosine
  • Phosphoproteins