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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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MG induced adipogenesis in 3T3-L1 adipocytes.After treated with MG, SH-6 or alagebrium for 48 h, cells were cultured till confluence and differentiation. The Oil Red O staining in adipocytes was shown in (A). The lipid content in adipocytes from different groups was quantified and presented as the percentage of that from control cells (B). The mRNA expression of adiponectin, PPARγ, C/EBPα and leptin in differentiated cells treated with MG alone or with MG and alagebrium were determined by real-time PCR (C). *P<0.05; **P<0.01; n = 3 in each groups. The open square in Figure 6C represents cells treated with MG; the stripped square represents cells treated with MG alagebrium. CT: control; ALA: alagebrium.
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pone-0036610-g006: MG induced adipogenesis in 3T3-L1 adipocytes.After treated with MG, SH-6 or alagebrium for 48 h, cells were cultured till confluence and differentiation. The Oil Red O staining in adipocytes was shown in (A). The lipid content in adipocytes from different groups was quantified and presented as the percentage of that from control cells (B). The mRNA expression of adiponectin, PPARγ, C/EBPα and leptin in differentiated cells treated with MG alone or with MG and alagebrium were determined by real-time PCR (C). *P<0.05; **P<0.01; n = 3 in each groups. The open square in Figure 6C represents cells treated with MG; the stripped square represents cells treated with MG alagebrium. CT: control; ALA: alagebrium.

Mentions: We have observed that incubation of 3T3-L1 cells with MG (10 µM) caused increased cell proliferation. To investigate whether this associates with a greater number of differentiated adipocytes, we treated the 3T3-L1 cells with MG, without or with SH-6 or alagebrium, for 48 h. On the 5th day of post-differentiation, triglyceride accumulation was indeed increased to 115.7±1.6% of the control level (Fig. 6A, B). The increased lipid content in MG-treated cells was attenuated by SH-6 or alagebrium co-administration. MG treatment (10–30 uM) of 3T3-L1 cells not only upregulates the transcriptional expression of adiponectin, leptin, PPARγ and C/EBPα, four important adipogenic markers, but also increases cellular adipogenesis (Fig. 6C). Furthermore, co-treatment of the cells with ALA efficiently reversed the MG-induced upregulation of these adipogenic markers.


Methylglyoxal mediates adipocyte proliferation by increasing phosphorylation of Akt1.

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

MG induced adipogenesis in 3T3-L1 adipocytes.After treated with MG, SH-6 or alagebrium for 48 h, cells were cultured till confluence and differentiation. The Oil Red O staining in adipocytes was shown in (A). The lipid content in adipocytes from different groups was quantified and presented as the percentage of that from control cells (B). The mRNA expression of adiponectin, PPARγ, C/EBPα and leptin in differentiated cells treated with MG alone or with MG and alagebrium were determined by real-time PCR (C). *P<0.05; **P<0.01; n = 3 in each groups. The open square in Figure 6C represents cells treated with MG; the stripped square represents cells treated with MG alagebrium. CT: control; ALA: alagebrium.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0036610-g006: MG induced adipogenesis in 3T3-L1 adipocytes.After treated with MG, SH-6 or alagebrium for 48 h, cells were cultured till confluence and differentiation. The Oil Red O staining in adipocytes was shown in (A). The lipid content in adipocytes from different groups was quantified and presented as the percentage of that from control cells (B). The mRNA expression of adiponectin, PPARγ, C/EBPα and leptin in differentiated cells treated with MG alone or with MG and alagebrium were determined by real-time PCR (C). *P<0.05; **P<0.01; n = 3 in each groups. The open square in Figure 6C represents cells treated with MG; the stripped square represents cells treated with MG alagebrium. CT: control; ALA: alagebrium.
Mentions: We have observed that incubation of 3T3-L1 cells with MG (10 µM) caused increased cell proliferation. To investigate whether this associates with a greater number of differentiated adipocytes, we treated the 3T3-L1 cells with MG, without or with SH-6 or alagebrium, for 48 h. On the 5th day of post-differentiation, triglyceride accumulation was indeed increased to 115.7±1.6% of the control level (Fig. 6A, B). The increased lipid content in MG-treated cells was attenuated by SH-6 or alagebrium co-administration. MG treatment (10–30 uM) of 3T3-L1 cells not only upregulates the transcriptional expression of adiponectin, leptin, PPARγ and C/EBPα, four important adipogenic markers, but also increases cellular adipogenesis (Fig. 6C). Furthermore, co-treatment of the cells with ALA efficiently reversed the MG-induced upregulation of these adipogenic markers.

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