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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

Sudachitin increases energy metabolism-related gene expressions by activating mitochondrial biogenesis. Relative mRNA expression of energy metabolism-related genes in the gastrocnemius muscle (A, B) and brown adipose tissue (A). Gene expression was normalized for GAPDH in both tissues. Phosphorylation of AMPK in sudachitin- or vehicle-treated mice with or without insulin (C). Protein expression of GLUT4 in mice administrated vehicle or sudachitin (D). Skeletal muscle ATP content in mice fed a high-fat diet and treated with sudachitin or vehicle (E). Citrate synthase activity was measured in mitochondria isolated from high-fat diet-fed mice treated with 5 mg/kg sudachitin or vehicle (F). Data are presented as mean ± standard deviation. *P < 0.05 vs. the indicated group. Closed bars; vehicle-treated group; open bars: sudachitin-treated group.
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Figure 8: Sudachitin increases energy metabolism-related gene expressions by activating mitochondrial biogenesis. Relative mRNA expression of energy metabolism-related genes in the gastrocnemius muscle (A, B) and brown adipose tissue (A). Gene expression was normalized for GAPDH in both tissues. Phosphorylation of AMPK in sudachitin- or vehicle-treated mice with or without insulin (C). Protein expression of GLUT4 in mice administrated vehicle or sudachitin (D). Skeletal muscle ATP content in mice fed a high-fat diet and treated with sudachitin or vehicle (E). Citrate synthase activity was measured in mitochondria isolated from high-fat diet-fed mice treated with 5 mg/kg sudachitin or vehicle (F). Data are presented as mean ± standard deviation. *P < 0.05 vs. the indicated group. Closed bars; vehicle-treated group; open bars: sudachitin-treated group.

Mentions: Because sudachitin increased adiponectin levels and reduced adiposity without reducing food intake, we hypothesized that sudachitin increases the energy expenditure. To assess whole-body energy expenditure, mice fed a high-fat diet were treated with sudachitin or vehicle and subjected to indirect calorimetry. Oxygen consumption during the light and dark cycles was increased by the administration of sudachitin for 4 weeks, without weight change compared with control mice, resulting in an increase in total daily energy expenditure by 45% compared with vehicle-treated mice (Figure 7A and B). We observed similar increases in energy expenditure in db/db mice after 4 weeks of administration of 5 mg/kg per day of sudachitin (Figure 7C-D).Interestingly, in mice fed a high-fat diet, the respiratory quotient was not markedly different between mice treated without or with sudachitin (0.87 ± 0.04 and 0.83 ± 0.03, respectively). Because energy expenditure can be increased by mitochondrial uncoupling, we examined the expression of UCP1–3 in the gastrocnemius muscle and in BAT (Figure 8A). There were no significant differences in UCP3 expression levels in any of the tissues, although its expression was slightly increased in the skeletal muscle of sudachitin-treated mice. By contrast, UCP2 gene expression was significantly increased in skeletal muscle of sudachitin-treated mice. Sudachitin also induced the expression of PGC-1α and its target gene Sirt1 in skeletal muscle, which are known to regulate energy metabolism (Figure 8B). As shown in Figures 8C and D, there was a statistically insignificant trend toward increased phosphorylation of AMP protein kinase (AMPK) and Glut4 expression in response to sudachitin treatment. We also observed a 1.3-fold increase in basal ATP content (Figure 8E), as well as increased citrate synthase activity (Figure 8F) in sudachitin-treated mice, consistent with enhanced mitochondrial content or activity.


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)

Sudachitin increases energy metabolism-related gene expressions by activating mitochondrial biogenesis. Relative mRNA expression of energy metabolism-related genes in the gastrocnemius muscle (A, B) and brown adipose tissue (A). Gene expression was normalized for GAPDH in both tissues. Phosphorylation of AMPK in sudachitin- or vehicle-treated mice with or without insulin (C). Protein expression of GLUT4 in mice administrated vehicle or sudachitin (D). Skeletal muscle ATP content in mice fed a high-fat diet and treated with sudachitin or vehicle (E). Citrate synthase activity was measured in mitochondria isolated from high-fat diet-fed mice treated with 5 mg/kg sudachitin or vehicle (F). Data are presented as mean ± standard deviation. *P < 0.05 vs. the indicated group. Closed bars; vehicle-treated group; open bars: sudachitin-treated group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4128574&req=5

Figure 8: Sudachitin increases energy metabolism-related gene expressions by activating mitochondrial biogenesis. Relative mRNA expression of energy metabolism-related genes in the gastrocnemius muscle (A, B) and brown adipose tissue (A). Gene expression was normalized for GAPDH in both tissues. Phosphorylation of AMPK in sudachitin- or vehicle-treated mice with or without insulin (C). Protein expression of GLUT4 in mice administrated vehicle or sudachitin (D). Skeletal muscle ATP content in mice fed a high-fat diet and treated with sudachitin or vehicle (E). Citrate synthase activity was measured in mitochondria isolated from high-fat diet-fed mice treated with 5 mg/kg sudachitin or vehicle (F). Data are presented as mean ± standard deviation. *P < 0.05 vs. the indicated group. Closed bars; vehicle-treated group; open bars: sudachitin-treated group.
Mentions: Because sudachitin increased adiponectin levels and reduced adiposity without reducing food intake, we hypothesized that sudachitin increases the energy expenditure. To assess whole-body energy expenditure, mice fed a high-fat diet were treated with sudachitin or vehicle and subjected to indirect calorimetry. Oxygen consumption during the light and dark cycles was increased by the administration of sudachitin for 4 weeks, without weight change compared with control mice, resulting in an increase in total daily energy expenditure by 45% compared with vehicle-treated mice (Figure 7A and B). We observed similar increases in energy expenditure in db/db mice after 4 weeks of administration of 5 mg/kg per day of sudachitin (Figure 7C-D).Interestingly, in mice fed a high-fat diet, the respiratory quotient was not markedly different between mice treated without or with sudachitin (0.87 ± 0.04 and 0.83 ± 0.03, respectively). Because energy expenditure can be increased by mitochondrial uncoupling, we examined the expression of UCP1–3 in the gastrocnemius muscle and in BAT (Figure 8A). There were no significant differences in UCP3 expression levels in any of the tissues, although its expression was slightly increased in the skeletal muscle of sudachitin-treated mice. By contrast, UCP2 gene expression was significantly increased in skeletal muscle of sudachitin-treated mice. Sudachitin also induced the expression of PGC-1α and its target gene Sirt1 in skeletal muscle, which are known to regulate energy metabolism (Figure 8B). As shown in Figures 8C and D, there was a statistically insignificant trend toward increased phosphorylation of AMP protein kinase (AMPK) and Glut4 expression in response to sudachitin treatment. We also observed a 1.3-fold increase in basal ATP content (Figure 8E), as well as increased citrate synthase activity (Figure 8F) in sudachitin-treated mice, consistent with enhanced mitochondrial content or activity.

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