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. 2017 Jan 17;18(1):168.
doi: 10.3390/ijms18010168.

6-Paradol and 6-Shogaol, the Pungent Compounds of Ginger, Promote Glucose Utilization in Adipocytes and Myotubes, and 6-Paradol Reduces Blood Glucose in High-Fat Diet-Fed Mice

Chien-Kei Wei  1 , Yi-Hong Tsai  2 , Michal Korinek  3 , Pei-Hsuan Hung  4 , Mohamed El-Shazly  5   6 , Yuan-Bin Cheng  7 , Yang-Chang Wu  8   9   10   11 , Tusty-Jiuan Hsieh  12   13   14   15 , Fang-Rong Chang  16   17   18
Affiliations

6-Paradol and 6-Shogaol, the Pungent Compounds of Ginger, Promote Glucose Utilization in Adipocytes and Myotubes, and 6-Paradol Reduces Blood Glucose in High-Fat Diet-Fed Mice

Chien-Kei Wei et al. Int J Mol Sci. .

Abstract

The anti-diabetic activity of ginger powder (Zingiber officinale) has been recently promoted, with the recommendation to be included as one of the dietary supplements for diabetic patients. However, previous studies presented different results, which may be caused by degradation and metabolic changes of ginger components, gingerols, shogaols and paradols. Therefore, we prepared 10 ginger active components, namely 6-, 8-, 10-paradols, 6-, 8-, 10-shogaols, 6-, 8-, 10-gingerols and zingerone, and evaluated their anti-hyperglycemic activity. Among the tested compounds, 6-paradol and 6-shogaol showed potent activity in stimulating glucose utilization by 3T3-L1 adipocytes and C2C12 myotubes. The effects were attributed to the increase in 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in 3T3-L1 adipocytes. 6-Paradol, the major metabolite of 6-shogaol, was utilized in an in vivo assay and significantly reduced blood glucose, cholesterol and body weight in high-fat diet-fed mice.

Keywords: 3T3-L1 adipocytes; 6-paradol; C2C12 myotubes; diabetes mellitus; high-fat diet-fed mice; shogaols.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Ginger non-volatile pungent components promote medium glucose consumption by 3T3-L1 adipocytes. (A) Chemical structures of ginger’s non-volatile pungent compounds used in this study; (B) Medium glucose consumption in 3T3-L1 adipocytes revealing the effect of ginger non-volatile pungent compounds (100 μM). The 3T3-L1 adipocytes were treated with the compounds without insulin in 450 mg/dL d-glucose Dulbecco’s modified Eagle’s medium (DMEM). After 24 h, the remaining glucose concentration of the medium was measured using chemistry analyzer. The data represent the amount of glucose in mg/dL consumed by the cells after 24 h of treatment. Data reflect the mean ± SEM of three independent experiments. a p < 0.001 and b p < 0.01 indicate a significant difference compared with the control group; (C) Cell viability of 3T3-L1 (left) and C2C12 (right) cells after the treatment with 50–400 μM of 6-paradol and 6-, 8-, 10-shogaols for 24 h. The cell viability was detected using water soluble tetrazolium salt (WST-1) reagent (Roche, Basel, Switzerland). Values are the mean ± SEM (n = 4). a p < 0.001 and b p < 0.01 compared to the control.
Figure 2
Figure 2
6-Shogaol promotes medium glucose consumption in 3T3-L1 adipocytes and C2C12 myotubes and inhibits lipid synthesis in 3T3-L1 adipocytes. Medium glucose consumption in 3T3-L1 adipocytes (A) or C2C12 myotubes (B) in response to the treatment of different concentrations of 6-shogaol and 6-gingerol without or with insulin (0.32 μM) in 450 mg/dL d-glucose DMEM. After 24 h, the remaining glucose concentration of the medium was measured using a chemistry analyzer. The data represent the amount of glucose in mg/dL consumed by the cells after 24 h of treatment. 6-Gingerol (100 μM) and pioglitazone (100 μM) were used as the positive controls. (C) Oil Red O staining of lipid droplets in 3T3-L1 adipocytes (magnification 200×). Data reflect the mean ± SEM of three independent experiments. The red arrows indicate examples of stained oil drops in adipocytes (see the control picture). a p < 0.001, b p < 0.01 and c p < 0.05 indicate a significant difference compared with the control group.
Figure 3
Figure 3
The effect of 6-, 8- or 10-shogaol on glucose utilization and lipid synthesis. Medium glucose consumption in 3T3-L1 adipocytes (A) or C2C12 myotubes (B) in response to the treatment with 6-, 8- or 10-shogaol. 3T3-L1 adipocytes or C2C12 myotubes were treated with the tested samples with or without insulin treatment (0.32 μM) in 450 mg/dL d-glucose DMEM. After 24 h, the remaining glucose concentration of the medium was analyzed using a chemistry analyzer. The data represent the amount of glucose in mg/dL consumed by the cells after 24 h of treatment. (C) Oil Red O staining and measurement of lipid content (magnification 200×). Data reflect the mean ± SEM of three independent experiments. a p < 0.001, b p < 0.01 and c p < 0.05 indicate a significant difference compared with the control group; d p < 0.001, e p < 0.01 and f p < 0.05 indicate a significant difference between the two compared groups.
Figure 4
Figure 4
The effect of 6-paradol on glucose utilization and lipid synthesis. Medium glucose consumption in 3T3-L1 adipocytes (A) or C2C12 myotubes (B) in response to the treatment with 6-paradol. 3T3-L1 adipocytes or C2C12 myotubes were treated with the tested samples with or without insulin (0.32 μM) in 450 mg/dL d-glucose DMEM. After 24 h, the remaining glucose concentration of the medium was measured using a chemistry analyzer. The data represent the amount of glucose in mg/dL consumed by the cells after 24 h of treatment. (C) Oil Red O staining and measurement of lipid content (magnification 200×). Results are the mean ± SEM of three independent experiments. a p < 0.001, b p < 0.01 and c p < 0.05 indicate a significant difference compared with the control group.
Figure 5
Figure 5
The effects of 6-shogaol on AKT and AMPK phosphorylation and aP2 protein expression and of 6-paradol on AMPK phosphorylation. (A) Differentiated 3T3-L1 adipocytes were treated with 6-shogaol or vehicle (control) for 48 h. Protein levels of P-AMPK, total-AMPK, P-AKT, total-AKT, aP2 and GAPDH were determined by Western blot analysis and expressed as a percentage of the control. (B) The effect of 6-shogaol on glucose consumption co-treated with specific kinase inhibitors of AMPK or AKT in 3T3-L1 cells. After 24 h, the remaining glucose concentration of the medium was measured using a chemistry analyzer. The data represent the amount of glucose in mg/dL consumed by the cells after 24 h of treatment. (C) Differentiated 3T3-L1 adipocytes were treated with 6-paradol or vehicle (control) for 48 h. Protein levels of P-AMPK and total-AMPK were determined by Western blot analysis and expressed as a percentage of the control. Results are the mean ± SEM of three independent experiments. a p < 0.001 and b p < 0.01 indicate a significant difference compared with the control group.
Figure 6
Figure 6
6-Paradol alleviates blood glucose and body weight in high-fat diet-fed mice. (A) Effect of 6-paradol on glucose tolerance in mice fasted for 2 h as determined by the oral glucose tolerance test (OGTT); (B) area under the curve (AUC) for the OGTT test; (C) body weight within eight weeks. Data reflect the mean ± SEM of three independent experiments. a p < 0.001, b p < 0.01 and c p < 0.05 indicate a significant difference compared with the HFD group. Control represents the group of normal- diet-fed mice (n = 9); HFD represents the group of high-fat diet-fed mice (n = 8); HFD + 6P 6.75 mg/kg/day represents the group of high-fat diet-fed mice fed with the 6-paradol (6.75 mg/kg/day) treatment (n = 7); HFD + 6P 33.75 mg/kg/day represents the group of high-fat diet-fed mice fed with the 6-paradol (33.75 mg/kg/day) treatment (n = 6); HFD + Pio. 6.75 mg/kg/day represents the group of high-fat diet-fed mice fed with the pioglitazone (6.75 mg/kg/day) treatment (n = 6).
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