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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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Increased MG accumulation, reduced GSH level and glyoxalase I activity were related to Akt1 expression in obese Zucker rats.(A) MG levels in kidney, fat, liver of 16-week old Zucker lean or obese rats. *P<0.05, n = 4−8 in each groups. (B) GSH level decreased in the adipose tissue of Zucker obese rats while glyoxalase I activity (C ) remain unchanged compare with Zucker lean rats. GSH level was presented as % of that in control group. *P<0.05, n = 4 in each groups. (D) The expression of p-Akt1 and Akt1 in adipose tissue of lean and obese Zucker rats. *P<0.05, **P<0.01, n = 4 in both groups. The results of Western blotting were quantified by Chemigenus® Bio imaging system company) and presented as the percentage of that from control cells (E). □ Zucker lean rats, ▪ Zucker obese rats.
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pone-0036610-g001: Increased MG accumulation, reduced GSH level and glyoxalase I activity were related to Akt1 expression in obese Zucker rats.(A) MG levels in kidney, fat, liver of 16-week old Zucker lean or obese rats. *P<0.05, n = 4−8 in each groups. (B) GSH level decreased in the adipose tissue of Zucker obese rats while glyoxalase I activity (C ) remain unchanged compare with Zucker lean rats. GSH level was presented as % of that in control group. *P<0.05, n = 4 in each groups. (D) The expression of p-Akt1 and Akt1 in adipose tissue of lean and obese Zucker rats. *P<0.05, **P<0.01, n = 4 in both groups. The results of Western blotting were quantified by Chemigenus® Bio imaging system company) and presented as the percentage of that from control cells (E). □ Zucker lean rats, ▪ Zucker obese rats.

Mentions: It was reported that plasma level of MG was increased in rats with diabetes and hypertension [12], [35], [36], [37], [38]. To examine the correlation between MG accumulation and the development of obesity, we compared the MG accumulation in the white fat tissues from Zucker lean and obese rats. At the age of 16 weeks, the body weight of the obese rats was significantly greater than that of the lean rats (Table 1), which is consistent with an increased adipose tissue deposit in obese rats (data not shown). Obese rats also exhibited higher serum triglyceride (TG), higher total cholesterol (Chol), but significantly decreased high-density cholesterol (HDL) level comparing with those of lean rats (Table 1). Although the fasting glucose level did not show significant difference between lean and obese rats at the ages of 10, 12, 14 and 16 weeks (Table 1), a markedly increased MG accumulation was observed in kidney, and fat tissue of obese rats at age of 16 weeks (Fig. 1A). In addition, MG level was shown accumulated in serum of obese rats (13.46±1.13 µM vs 4.08±0.94 µM in lean rats). With the increased MG accumulation, a decreased GSH level was observed in obese rats (Fig. 1B). However, the activity of glyoxalase I, the major enzyme detoxifying MG, did not show significant change (Fig. 1C), suggesting that elevated MG level may be mainly related to MG formation.


Methylglyoxal mediates adipocyte proliferation by increasing phosphorylation of Akt1.

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

Increased MG accumulation, reduced GSH level and glyoxalase I activity were related to Akt1 expression in obese Zucker rats.(A) MG levels in kidney, fat, liver of 16-week old Zucker lean or obese rats. *P<0.05, n = 4−8 in each groups. (B) GSH level decreased in the adipose tissue of Zucker obese rats while glyoxalase I activity (C ) remain unchanged compare with Zucker lean rats. GSH level was presented as % of that in control group. *P<0.05, n = 4 in each groups. (D) The expression of p-Akt1 and Akt1 in adipose tissue of lean and obese Zucker rats. *P<0.05, **P<0.01, n = 4 in both groups. The results of Western blotting were quantified by Chemigenus® Bio imaging system company) and presented as the percentage of that from control cells (E). □ Zucker lean rats, ▪ Zucker obese rats.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0036610-g001: Increased MG accumulation, reduced GSH level and glyoxalase I activity were related to Akt1 expression in obese Zucker rats.(A) MG levels in kidney, fat, liver of 16-week old Zucker lean or obese rats. *P<0.05, n = 4−8 in each groups. (B) GSH level decreased in the adipose tissue of Zucker obese rats while glyoxalase I activity (C ) remain unchanged compare with Zucker lean rats. GSH level was presented as % of that in control group. *P<0.05, n = 4 in each groups. (D) The expression of p-Akt1 and Akt1 in adipose tissue of lean and obese Zucker rats. *P<0.05, **P<0.01, n = 4 in both groups. The results of Western blotting were quantified by Chemigenus® Bio imaging system company) and presented as the percentage of that from control cells (E). □ Zucker lean rats, ▪ Zucker obese rats.
Mentions: It was reported that plasma level of MG was increased in rats with diabetes and hypertension [12], [35], [36], [37], [38]. To examine the correlation between MG accumulation and the development of obesity, we compared the MG accumulation in the white fat tissues from Zucker lean and obese rats. At the age of 16 weeks, the body weight of the obese rats was significantly greater than that of the lean rats (Table 1), which is consistent with an increased adipose tissue deposit in obese rats (data not shown). Obese rats also exhibited higher serum triglyceride (TG), higher total cholesterol (Chol), but significantly decreased high-density cholesterol (HDL) level comparing with those of lean rats (Table 1). Although the fasting glucose level did not show significant difference between lean and obese rats at the ages of 10, 12, 14 and 16 weeks (Table 1), a markedly increased MG accumulation was observed in kidney, and fat tissue of obese rats at age of 16 weeks (Fig. 1A). In addition, MG level was shown accumulated in serum of obese rats (13.46±1.13 µM vs 4.08±0.94 µM in lean rats). With the increased MG accumulation, a decreased GSH level was observed in obese rats (Fig. 1B). However, the activity of glyoxalase I, the major enzyme detoxifying MG, did not show significant change (Fig. 1C), suggesting that elevated MG level may be mainly related to MG formation.

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