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Methylglyoxal mediates adipocyte proliferation by increasing phosphorylation of Akt1.

Jia X, Chang T, Wilson TW, Wu L - PLoS ONE (2012)

Bottom Line: The effects of MG on diabetes and hypertension have been long recognized.The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells.The effects of MG were efficiently reversed by advanced glycation end product (AGE) breaker alagebrium and Akt inhibitor SH-6.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Collage of Medicine, University of Saskatchewan, Saskatoon, Canada.

ABSTRACT
Methylglyoxal (MG) is a highly reactive metabolite physiologically presented in all biological systems. The effects of MG on diabetes and hypertension have been long recognized. In the present study, we investigated the potential role of MG in obesity, one of the most important factors to cause metabolic syndrome. An increased MG accumulation was observed in the adipose tissue of obese Zucker rats. Cell proliferation assay showed that 5-20 µM of MG stimulated the proliferation of 3T3-L1 cells. Further study suggested that accumulated-MG stimulated the phosphorylation of Akt1 and its targets including p21 and p27. The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells. The effects of MG were efficiently reversed by advanced glycation end product (AGE) breaker alagebrium and Akt inhibitor SH-6. In summary, our study revealed a previously unrecognized effect of MG in stimulating adipogenesis by up-regulation of Akt signaling pathway and this mechanism might offer a new approach to explain the development of obesity.

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Related in: MedlinePlus

Effect of MG on cell cycle progression of 3T3-L1 cells.After 12, 16, 20 h of MG (10 µM) treatment, cellular DNA content was determined by a flow cytometer (A). The effect of MG with/without SH6 (10 µM) or alagebrium (50 µM) on cellular DNA content is shown in (B). *P<0.05 vs control group; +P<0.05 vs MG treated group; n = 6 in each group. The indicated percentage of the cell number is average of three experiments. CT: control; ALA: alagebrium.
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pone-0036610-g003: Effect of MG on cell cycle progression of 3T3-L1 cells.After 12, 16, 20 h of MG (10 µM) treatment, cellular DNA content was determined by a flow cytometer (A). The effect of MG with/without SH6 (10 µM) or alagebrium (50 µM) on cellular DNA content is shown in (B). *P<0.05 vs control group; +P<0.05 vs MG treated group; n = 6 in each group. The indicated percentage of the cell number is average of three experiments. CT: control; ALA: alagebrium.

Mentions: The effect of MG on cell proliferation was further confirmed by analysis of the cell cycle phase distribution after MG treatment (Fig. 3). Comparing the cell number distributed in G1, S and G2 cell phase at different time points, we found that the MG-treatment lead to a faster cell cycle progression (Fig. 3A), which represented as an increased cell number in S phase after 16 or 20 h of MG (10 µM) treatment (Fig. 3A–b) and increased cell number in G2 phase after exposure of cells to MG (10 µM) for 20 h (Fig. 3A–c). The co-administration of SH-6 (10 µM) reversed the effect of MG on cell cycle progression in S and G2 phases (Fig. 3B–b, c). In contrast, increased G1 phase distribution indicated a longer interdivision time due to the inhibited rate of mass synthesis in cells co-treated with MG and SH-6, which reflects the inhibitive effect of SH-6 on Akt. Correspondingly, there was an increase of S phase cell number in cells treated with MG alone (Fig. 3B–b). Although reported to induce cell apoptosis at higher concentrations, 10 µM of MG did not increase sub-diploid/apoptotic cells. The percentage of apoptotic cells was 2.57%, 2.74%, 2.66% and 2.45% respectively for control group, MG-treated group, MG-SH6 and MG-ALA group.


Methylglyoxal mediates adipocyte proliferation by increasing phosphorylation of Akt1.

Jia X, Chang T, Wilson TW, Wu L - PLoS ONE (2012)

Effect of MG on cell cycle progression of 3T3-L1 cells.After 12, 16, 20 h of MG (10 µM) treatment, cellular DNA content was determined by a flow cytometer (A). The effect of MG with/without SH6 (10 µM) or alagebrium (50 µM) on cellular DNA content is shown in (B). *P<0.05 vs control group; +P<0.05 vs MG treated group; n = 6 in each group. The indicated percentage of the cell number is average of three experiments. CT: control; ALA: alagebrium.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351465&req=5

pone-0036610-g003: Effect of MG on cell cycle progression of 3T3-L1 cells.After 12, 16, 20 h of MG (10 µM) treatment, cellular DNA content was determined by a flow cytometer (A). The effect of MG with/without SH6 (10 µM) or alagebrium (50 µM) on cellular DNA content is shown in (B). *P<0.05 vs control group; +P<0.05 vs MG treated group; n = 6 in each group. The indicated percentage of the cell number is average of three experiments. CT: control; ALA: alagebrium.
Mentions: The effect of MG on cell proliferation was further confirmed by analysis of the cell cycle phase distribution after MG treatment (Fig. 3). Comparing the cell number distributed in G1, S and G2 cell phase at different time points, we found that the MG-treatment lead to a faster cell cycle progression (Fig. 3A), which represented as an increased cell number in S phase after 16 or 20 h of MG (10 µM) treatment (Fig. 3A–b) and increased cell number in G2 phase after exposure of cells to MG (10 µM) for 20 h (Fig. 3A–c). The co-administration of SH-6 (10 µM) reversed the effect of MG on cell cycle progression in S and G2 phases (Fig. 3B–b, c). In contrast, increased G1 phase distribution indicated a longer interdivision time due to the inhibited rate of mass synthesis in cells co-treated with MG and SH-6, which reflects the inhibitive effect of SH-6 on Akt. Correspondingly, there was an increase of S phase cell number in cells treated with MG alone (Fig. 3B–b). Although reported to induce cell apoptosis at higher concentrations, 10 µM of MG did not increase sub-diploid/apoptotic cells. The percentage of apoptotic cells was 2.57%, 2.74%, 2.66% and 2.45% respectively for control group, MG-treated group, MG-SH6 and MG-ALA group.

Bottom Line: The effects of MG on diabetes and hypertension have been long recognized.The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells.The effects of MG were efficiently reversed by advanced glycation end product (AGE) breaker alagebrium and Akt inhibitor SH-6.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Collage of Medicine, University of Saskatchewan, Saskatoon, Canada.

ABSTRACT
Methylglyoxal (MG) is a highly reactive metabolite physiologically presented in all biological systems. The effects of MG on diabetes and hypertension have been long recognized. In the present study, we investigated the potential role of MG in obesity, one of the most important factors to cause metabolic syndrome. An increased MG accumulation was observed in the adipose tissue of obese Zucker rats. Cell proliferation assay showed that 5-20 µM of MG stimulated the proliferation of 3T3-L1 cells. Further study suggested that accumulated-MG stimulated the phosphorylation of Akt1 and its targets including p21 and p27. The activated Akt1 then increased the activity of CDK2 and accelerated the cell cycle progression of 3T3-L1 cells. The effects of MG were efficiently reversed by advanced glycation end product (AGE) breaker alagebrium and Akt inhibitor SH-6. In summary, our study revealed a previously unrecognized effect of MG in stimulating adipogenesis by up-regulation of Akt signaling pathway and this mechanism might offer a new approach to explain the development of obesity.

Show MeSH
Related in: MedlinePlus