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Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle.

Tsutsumi R, Yoshida T, Nii Y, Okahisa N, Iwata S, Tsukayama M, Hashimoto R, Taniguchi Y, Sakaue H, Hosaka T, Shuto E, Sakai T - Nutr Metab (Lond) (2014)

Bottom Line: Flavonoids are effective antioxidants that protect against these chronic diseases.Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance.The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Public Health and Applied and Nutrition, Institute of Health Bioscience, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.

ABSTRACT

Background: Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain.

Methods: C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro.

Results: Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid β-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle.

Conclusions: Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders.

No MeSH data available.


Related in: MedlinePlus

Effects of sudachitin on gene expression in mouse primary skeletal muscle myocytes in vitro. Gene transcription in myocytes treated with 30 μmol/L sudachitin or vehicle for 48 h, normalized for β-actin (A). Data are means ± standard deviation. *P < 0.05 vs the indicated group. Closed bars: untreated cells; open bars: sudachitin-treated cells. The number of mitochondria in myocytes was increased by sudachitin (B, C). Myocytes were incubated with the fluorophore Mito-Tracker Green, which specifically labels mitochondria. Upper panel: control cells; lower panel: cells treated with 30 μmol/L sudachitin for 48 h. Arrows indicate stained mitochondria (B). Quantitative analysis of mitochondrial staining. Fluorescence intensity was measured by ImageJ software using the analyze particle function. *P < 0.05.
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Figure 9: Effects of sudachitin on gene expression in mouse primary skeletal muscle myocytes in vitro. Gene transcription in myocytes treated with 30 μmol/L sudachitin or vehicle for 48 h, normalized for β-actin (A). Data are means ± standard deviation. *P < 0.05 vs the indicated group. Closed bars: untreated cells; open bars: sudachitin-treated cells. The number of mitochondria in myocytes was increased by sudachitin (B, C). Myocytes were incubated with the fluorophore Mito-Tracker Green, which specifically labels mitochondria. Upper panel: control cells; lower panel: cells treated with 30 μmol/L sudachitin for 48 h. Arrows indicate stained mitochondria (B). Quantitative analysis of mitochondrial staining. Fluorescence intensity was measured by ImageJ software using the analyze particle function. *P < 0.05.

Mentions: To determine the direct effects of sudachitin on muscle metabolism, we assessed the expression of key genes and mitochondrial number in vitro in primary cultured myocytes following incubation with sudachitin. Consistent with the observed increase in PGC-1α and Sirt1 mRNA in mice (Figure 8), transcription of these genes was significantly increased in differentiated myocytes exposed to 30 μmol/L sudachitin compared with the vehicle-treated cells (Figure 9A). Considering the genes involved in mitochondrial biogenesis, the expression of NRF1, NRF2, and mtTFA were increased by 1.5- to 2.5-fold following sudachitin treatment. In addition, the expression of UCP2 was significantly increased and UCP3 expression was slightly increased in myocytes treated with sudachitin for 48 h, whereas UCP1 was not different between control and sudachitin-treated myocytes. Because GLUT4 expression was increased in sudachitin-treated mice, we also determined the expressions of GLUT1, 3, and 4. As shown in Figure 9A, only the insulin insensitive transporters GLUT1 and 3 were significantly increased by sudachitin, whereas GLUT4 expression was not affected. To examine the effects of sudachitin on mitochondrial number and activity, we stained the mitochondria of myocytes and present representative images in Figure 9B and C, with stained mitochondria indicated with arrows. Sudachitin treatment increased mitochondrial staining with the fluorophore Mito-Tracker Green in skeletal muscle myocytes approximately 2.5-fold, in comparison to the cells treated with vehicle.


Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle.

Tsutsumi R, Yoshida T, Nii Y, Okahisa N, Iwata S, Tsukayama M, Hashimoto R, Taniguchi Y, Sakaue H, Hosaka T, Shuto E, Sakai T - Nutr Metab (Lond) (2014)

Effects of sudachitin on gene expression in mouse primary skeletal muscle myocytes in vitro. Gene transcription in myocytes treated with 30 μmol/L sudachitin or vehicle for 48 h, normalized for β-actin (A). Data are means ± standard deviation. *P < 0.05 vs the indicated group. Closed bars: untreated cells; open bars: sudachitin-treated cells. The number of mitochondria in myocytes was increased by sudachitin (B, C). Myocytes were incubated with the fluorophore Mito-Tracker Green, which specifically labels mitochondria. Upper panel: control cells; lower panel: cells treated with 30 μmol/L sudachitin for 48 h. Arrows indicate stained mitochondria (B). Quantitative analysis of mitochondrial staining. Fluorescence intensity was measured by ImageJ software using the analyze particle function. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4128574&req=5

Figure 9: Effects of sudachitin on gene expression in mouse primary skeletal muscle myocytes in vitro. Gene transcription in myocytes treated with 30 μmol/L sudachitin or vehicle for 48 h, normalized for β-actin (A). Data are means ± standard deviation. *P < 0.05 vs the indicated group. Closed bars: untreated cells; open bars: sudachitin-treated cells. The number of mitochondria in myocytes was increased by sudachitin (B, C). Myocytes were incubated with the fluorophore Mito-Tracker Green, which specifically labels mitochondria. Upper panel: control cells; lower panel: cells treated with 30 μmol/L sudachitin for 48 h. Arrows indicate stained mitochondria (B). Quantitative analysis of mitochondrial staining. Fluorescence intensity was measured by ImageJ software using the analyze particle function. *P < 0.05.
Mentions: To determine the direct effects of sudachitin on muscle metabolism, we assessed the expression of key genes and mitochondrial number in vitro in primary cultured myocytes following incubation with sudachitin. Consistent with the observed increase in PGC-1α and Sirt1 mRNA in mice (Figure 8), transcription of these genes was significantly increased in differentiated myocytes exposed to 30 μmol/L sudachitin compared with the vehicle-treated cells (Figure 9A). Considering the genes involved in mitochondrial biogenesis, the expression of NRF1, NRF2, and mtTFA were increased by 1.5- to 2.5-fold following sudachitin treatment. In addition, the expression of UCP2 was significantly increased and UCP3 expression was slightly increased in myocytes treated with sudachitin for 48 h, whereas UCP1 was not different between control and sudachitin-treated myocytes. Because GLUT4 expression was increased in sudachitin-treated mice, we also determined the expressions of GLUT1, 3, and 4. As shown in Figure 9A, only the insulin insensitive transporters GLUT1 and 3 were significantly increased by sudachitin, whereas GLUT4 expression was not affected. To examine the effects of sudachitin on mitochondrial number and activity, we stained the mitochondria of myocytes and present representative images in Figure 9B and C, with stained mitochondria indicated with arrows. Sudachitin treatment increased mitochondrial staining with the fluorophore Mito-Tracker Green in skeletal muscle myocytes approximately 2.5-fold, in comparison to the cells treated with vehicle.

Bottom Line: Flavonoids are effective antioxidants that protect against these chronic diseases.Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance.The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Public Health and Applied and Nutrition, Institute of Health Bioscience, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.

ABSTRACT

Background: Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain.

Methods: C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro.

Results: Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid β-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle.

Conclusions: Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders.

No MeSH data available.


Related in: MedlinePlus