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Protopanaxatriol, a novel PPARγ antagonist from Panax ginseng, alleviates steatosis in mice.

Zhang Y, Yu L, Cai W, Fan S, Feng L, Ji G, Huang C - Sci Rep (2014)

Bottom Line: Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis.TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study.Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.

ABSTRACT
Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis. Ginseng has been used as food and traditional herbal medicine for the treatment of various metabolic diseases. However, the molecular mechanisms how ginseng and its components participate in the regulation of lipogenesis are still largely unclear. Here, we identified that protopanaxatriol (PPT), a major ginseng constituent, inhibited rosiglitazone-supported adipocyte differentiation of 3T3-L1 cells by repressing the expression of lipogenesis-related gene expression. In high-fat diet-induced obesity (DIO) mice, PPT reduced body weight and serum lipid levels, improved insulin resistance, as well as morphology and lipid accumulation, particular macrovesicular steatosis, in the livers. These effects were confirmed with genetically obese ob/ob mice. A reporter gene assay showed that PPT specifically inhibited the transactivity of PPARγ, but not PPAR α, β/δ and LXR α, β. TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study. Our data demonstrate that PPT is a novel PPARγ antagonist. The inhibition of PPARγ activity could be a promising therapy for obesity and steatosis. Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

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PPT inhibits 3T3-L1 adipocyte differentiation and adipogenesis related gene expression.(a) Structure of PPT. (b) PPT suppresses 3T3-L1 adipocyte differentiation induced by differentiation medium. Differentiation medium includes 10 μg/ml insulin, 1 μM dexamethasone and 10 μM rosiglitazone. Oil red O staining of 3T3-L1 cells was performed on day 6. PPT was added to the medium at the beginning of induction of 3T3-L1 cells at the indicated concentration. (c) Real-time RT-PCR results of gene expression levels at day 0 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiation medium after confluence for 2 days. (d) Real-time RT-PCR results of gene expression levels at day 6 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiated for 6 days. Control: growth medium. I+D: insulin and dexamethasone. I+D+R: insulin, dexamethasone and rosiglitazone. Mouse beta-actin was used as the control and values representing mRNA of the untreated cells were defined as 1. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01.
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f1: PPT inhibits 3T3-L1 adipocyte differentiation and adipogenesis related gene expression.(a) Structure of PPT. (b) PPT suppresses 3T3-L1 adipocyte differentiation induced by differentiation medium. Differentiation medium includes 10 μg/ml insulin, 1 μM dexamethasone and 10 μM rosiglitazone. Oil red O staining of 3T3-L1 cells was performed on day 6. PPT was added to the medium at the beginning of induction of 3T3-L1 cells at the indicated concentration. (c) Real-time RT-PCR results of gene expression levels at day 0 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiation medium after confluence for 2 days. (d) Real-time RT-PCR results of gene expression levels at day 6 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiated for 6 days. Control: growth medium. I+D: insulin and dexamethasone. I+D+R: insulin, dexamethasone and rosiglitazone. Mouse beta-actin was used as the control and values representing mRNA of the untreated cells were defined as 1. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01.

Mentions: Since ginseng has been used for weight-reducing purposes in obese patients, we first asked whether the monoglucoside of ginseng was able to inhibit adipocyte differentiation. A 3T3-L1 adipocyte differentiation model was used in the study, and 20 monoglucosides purified from ginseng were screened to identify their ability to regulate lipogenesis and adipocyte differentiation. The results showed that PPT, Rg1 and Rb1 could suppress the lipogenesis and adipocyte differentiation (Table 1). PPT (Fig. 1a) is a major monoglucoside of Rg1 ginseng ginsenosides following metabolism by intestinal bacteria in humans. Therefore, we focused on PPT in the study due to its lipogenesis inhibitory effect.


Protopanaxatriol, a novel PPARγ antagonist from Panax ginseng, alleviates steatosis in mice.

Zhang Y, Yu L, Cai W, Fan S, Feng L, Ji G, Huang C - Sci Rep (2014)

PPT inhibits 3T3-L1 adipocyte differentiation and adipogenesis related gene expression.(a) Structure of PPT. (b) PPT suppresses 3T3-L1 adipocyte differentiation induced by differentiation medium. Differentiation medium includes 10 μg/ml insulin, 1 μM dexamethasone and 10 μM rosiglitazone. Oil red O staining of 3T3-L1 cells was performed on day 6. PPT was added to the medium at the beginning of induction of 3T3-L1 cells at the indicated concentration. (c) Real-time RT-PCR results of gene expression levels at day 0 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiation medium after confluence for 2 days. (d) Real-time RT-PCR results of gene expression levels at day 6 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiated for 6 days. Control: growth medium. I+D: insulin and dexamethasone. I+D+R: insulin, dexamethasone and rosiglitazone. Mouse beta-actin was used as the control and values representing mRNA of the untreated cells were defined as 1. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4260220&req=5

f1: PPT inhibits 3T3-L1 adipocyte differentiation and adipogenesis related gene expression.(a) Structure of PPT. (b) PPT suppresses 3T3-L1 adipocyte differentiation induced by differentiation medium. Differentiation medium includes 10 μg/ml insulin, 1 μM dexamethasone and 10 μM rosiglitazone. Oil red O staining of 3T3-L1 cells was performed on day 6. PPT was added to the medium at the beginning of induction of 3T3-L1 cells at the indicated concentration. (c) Real-time RT-PCR results of gene expression levels at day 0 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiation medium after confluence for 2 days. (d) Real-time RT-PCR results of gene expression levels at day 6 in 3T3-L1 adipocyte. Cells were treated with PPT (50 μM) and differentiated for 6 days. Control: growth medium. I+D: insulin and dexamethasone. I+D+R: insulin, dexamethasone and rosiglitazone. Mouse beta-actin was used as the control and values representing mRNA of the untreated cells were defined as 1. Data are presented as means ± SEM (n = 3). *P<0.05, **P<0.01.
Mentions: Since ginseng has been used for weight-reducing purposes in obese patients, we first asked whether the monoglucoside of ginseng was able to inhibit adipocyte differentiation. A 3T3-L1 adipocyte differentiation model was used in the study, and 20 monoglucosides purified from ginseng were screened to identify their ability to regulate lipogenesis and adipocyte differentiation. The results showed that PPT, Rg1 and Rb1 could suppress the lipogenesis and adipocyte differentiation (Table 1). PPT (Fig. 1a) is a major monoglucoside of Rg1 ginseng ginsenosides following metabolism by intestinal bacteria in humans. Therefore, we focused on PPT in the study due to its lipogenesis inhibitory effect.

Bottom Line: Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis.TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study.Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.

ABSTRACT
Obesity is prevalent worldwide, and is highly associated with metabolic disorders, such as insulin resistance, hyperlipidemia and steatosis. Ginseng has been used as food and traditional herbal medicine for the treatment of various metabolic diseases. However, the molecular mechanisms how ginseng and its components participate in the regulation of lipogenesis are still largely unclear. Here, we identified that protopanaxatriol (PPT), a major ginseng constituent, inhibited rosiglitazone-supported adipocyte differentiation of 3T3-L1 cells by repressing the expression of lipogenesis-related gene expression. In high-fat diet-induced obesity (DIO) mice, PPT reduced body weight and serum lipid levels, improved insulin resistance, as well as morphology and lipid accumulation, particular macrovesicular steatosis, in the livers. These effects were confirmed with genetically obese ob/ob mice. A reporter gene assay showed that PPT specifically inhibited the transactivity of PPARγ, but not PPAR α, β/δ and LXR α, β. TR-FRET assay revealed that PPT was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study. Our data demonstrate that PPT is a novel PPARγ antagonist. The inhibition of PPARγ activity could be a promising therapy for obesity and steatosis. Our findings shed new light on the mechanism of ginseng in the treatment of metabolic syndrome.

Show MeSH
Related in: MedlinePlus