Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism – What We Know in Mammals and What We Can Learn From Yeast

Zemva, Johanna; Pfaff, Daniel; Groener, Jan B.; Fleming, Thomas; Herzig, Stephan; Teleman, Aurelio A.; Nawroth, Peter P.; Tyedmers, Jens

doi:10.1055/s-0043-122382

Cited by 10 publications

(6 citation statements)

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“…MG is involved in the activation of signaling pathways as a signaling molecule in diverse organisms from yeast to mammalian cells [ 7 , 9 ]. Moreover, MG induces the activation of JNK, p38, and extracellular receptor kinase (ERK) MAPK signaling pathways in cultured cells [ [32] , [33] , [34] ].…”

Section: Resultsmentioning

confidence: 99%

“…Although the development of diabetic complications is the result of a highly complex process, the accumulation of advanced glycation end products (AGEs), the synthesis of which is initiated by a non-enzymatic reaction between the aldehyde groups of glucose and amino groups of proteins, is recognized as one of the major factors linked to it [ 6 ]. Methylglyoxal (MG, CH 3 COCHO) is a ubiquitous 2-oxoaldehyde derived from glycolysis [ [7] , [8] , [9] ]. Although MG is a natural metabolite, it is highly reactive because it contains two carbonyl groups and has a higher potential than glucose to produce AGEs.…”

Section: Introductionmentioning

confidence: 99%

“…Plasma and tissue MG levels are higher in patients with diabetes than in healthy individuals, suggesting that MG plays a role in the development and progression of diabetic complications [ [10] , [11] , [12] ]. MG is mainly metabolized to d -lactate within cells through a ubiquitous glutathione-dependent glyoxalase system consisting of glyoxalase I and glyoxalase II [ 7 , 9 ]. Functional genome analyses suggest a relationship between a deficiency in this system, which implies increased MG and the development of diabetic complications [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal attenuates isoproterenol-induced increase in uncoupling protein 1 expression through activation of JNK signaling pathway in beige adipocytes

Nomura

Takahashi

et al. 2021

Biochemistry and Biophysics Reports

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Methylglyoxal (MG) is a metabolite derived from glycolysis whose levels in the blood and tissues of patients with diabetes are higher than those of healthy individuals, suggesting that MG is associated with the development of diabetic complications. However, it remains unknown whether high levels of MG are a cause or consequence of diabetes. Here, we show that MG negatively affects the expression of uncoupling protein 1 (UCP1), which is involved in thermogenesis and the regulation of systemic metabolism. Decreased Ucp1 expression is associated with obesity and type 2 diabetes. We found that MG attenuated the increase in Ucp1 expression following treatment with isoproterenol in beige adipocytes. However, MG did not affect protein kinase A signaling, the core coordinator of isoproterenol-induced Ucp1 expression. Instead, MG activated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases. We found that JNK inhibition, but not p38, recovered isoproterenol-stimulated Ucp1 expression under MG treatment. Altogether, these results suggest an inhibitory role of MG on the thermogenic function of beige adipocytes through the JNK signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal attenuates isoproterenol-induced increase in uncoupling protein 1 expression through activation of JNK signaling pathway in beige adipocytes

Nomura

Takahashi

et al. 2021

Biochemistry and Biophysics Reports

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“…MG accumulation in adipocytes after exposure to MG causes structural and functional changes in adipose tissue [ 4 ] independently of obesity; these alterations may precede the onset of metabolic syndrome and type 2 diabetes (T2D). Indirectly, MG can disturb and impair different signaling pathways and also trigger epigenetic changes [ 12 ]. However, the exact mechanism underlying the pathophysiological role of MG and glyoxalase-1 in adipose tissue is not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Adverse Effects of Methylglyoxal on Transcriptome and Metabolic Changes in Visceral Adipose Tissue in a Prediabetic Rat Model

et al. 2020

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Excessive methylglyoxal (MG) production contributes to metabolic and vascular changes by increasing inflammatory processes, disturbing regulatory mechanisms and exacerbating tissue dysfunction. MG accumulation in adipocytes leads to structural and functional changes. We used transcriptome analysis to investigate the effect of MG on metabolic changes in the visceral adipose tissue of hereditary hypetriglyceridaemic rats, a non-obese model of metabolic syndrome. Compared to controls, 4-week intragastric MG administration impaired glucose tolerance (p < 0.05) and increased glycaemia (p < 0.01) and serum levels of MCP-1 and TNFα (p < 0.05), but had no effect on serum adiponectin or leptin. Adipose tissue insulin sensitivity and lipolysis were impaired (p < 0.05) in MG-treated rats. In addition, MG reduced the expression of transcription factor Nrf2 (p < 0.01), which controls antioxidant and lipogenic genes. Increased expression of Mcp-1 and TNFα (p < 0.05) together with activation of the SAPK/JNK signaling pathway can promote chronic inflammation in adipose tissue. Transcriptome network analysis revealed the over-representation of genes involved in insulin signaling (Irs1, Igf2, Ide), lipid metabolism (Nr1d1, Lpin1, Lrpap1) and angiogenesis (Dusp10, Tp53inp1).

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“…Methylglyoxal (MG) is a typical 2-oxoaldehyde derived from glycolysis 3 – 5 . Despite being a natural metabolite, MG at high concentrations inhibits the growth of cells in all types of organisms; however, precisely how it exerts its toxicity is unclear.…”

Section: Introductionmentioning

confidence: 99%

Methylglyoxal inhibits nuclear division through alterations in vacuolar morphology and accumulation of Atg18 on the vacuolar membrane in Saccharomyces cerevisiae

Nomura

Aoki

Inoue

2020

Sci Rep

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Methylglyoxal (MG) is a natural metabolite derived from glycolysis, and it inhibits the growth of cells in all kinds of organisms. We recently reported that MG inhibits nuclear division in Saccharomyces cerevisiae. However, the mechanism by which MG blocks nuclear division remains unclear. Here, we show that increase in the levels of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P 2) is crucial for the inhibitory effects of MG on nuclear division, and the deletion of PtdIns(3,5)P 2-effector Atg18 alleviated the MG-mediated inhibitory effects. Previously, we reported that MG altered morphology of the vacuole to a single swelling form, where PtdIns(3,5)P 2 accumulates. The changes in the vacuolar morphology were also needed by MG to exert its inhibitory effects on nuclear division. The known checkpoint machinery, including the spindle assembly checkpoint and morphological checkpoint, are not involved in the blockade of nuclear division by MG. Our results suggest that both the accumulation of Atg18 on the vacuolar membrane and alterations in vacuolar morphology are necessary for the MG-induced inhibition of nuclear division. Abbreviations MG Methylglyoxal PtdIns(3,5)P 2 Phosphatidylinositol 3,5-bisphosphate SD Synthetic dextrose SPB Spindle pole body The inheritance of chromosomes is a critical biological event for all organisms. Eukaryotic cells contain chromosomal DNA in the nucleus, an organelle enveloped in a double lipid bilayer (nuclear membrane). Unlike higher eukaryotes, the nuclear membrane in yeast cells is not degraded during mitosis (closed mitosis); therefore, the nucleus is transported to the daughter cell during the mitotic process 1. The budding yeast Saccharomyces cerevisiae is excellent for observing this process. A bud (daughter cell) begins to emerge from the mother cell at S phase and grows larger at M phase. The nuclear membrane is extended, a portion of the nucleus penetrates the bud, and then the nucleus is separated in the late M phase. Consequently, a set of chromosomes is inherited to the bud 2. Methylglyoxal (MG) is a typical 2-oxoaldehyde derived from glycolysis 3-5. Despite being a natural metabolite, MG at high concentrations inhibits the growth of cells in all types of organisms; however, precisely how it exerts its toxicity is unclear. Since MG enhances the frequency of sister chromatid exchange and endoreduplication in CHO-AUXBI cells 6 , it may have some effect on chromatin maintenance and inheritance. However, treatment

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Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism – What We Know in Mammals and What We Can Learn From Yeast

Cited by 10 publications

References 118 publications

Methylglyoxal attenuates isoproterenol-induced increase in uncoupling protein 1 expression through activation of JNK signaling pathway in beige adipocytes

Methylglyoxal attenuates isoproterenol-induced increase in uncoupling protein 1 expression through activation of JNK signaling pathway in beige adipocytes

Adverse Effects of Methylglyoxal on Transcriptome and Metabolic Changes in Visceral Adipose Tissue in a Prediabetic Rat Model

Methylglyoxal inhibits nuclear division through alterations in vacuolar morphology and accumulation of Atg18 on the vacuolar membrane in Saccharomyces cerevisiae

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