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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 mRNA levels in white adipose tissue and liver. Gene transcription was normalized for 36B4 in subcutaneous white adipose tissue (A-B) or 18S in liver (C). Data are means ± standard deviation. *P < 0.05 vs the indicated groups. Closed bars: vehicle-treated, high-fat diet group; open bars: sudachitin-treated, high-fat diet group.
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Figure 5: Effects of sudachitin on mRNA levels in white adipose tissue and liver. Gene transcription was normalized for 36B4 in subcutaneous white adipose tissue (A-B) or 18S in liver (C). Data are means ± standard deviation. *P < 0.05 vs the indicated groups. Closed bars: vehicle-treated, high-fat diet group; open bars: sudachitin-treated, high-fat diet group.

Mentions: As shown in Figure 5A, GLUT4 mRNA levels were significantly increased by the sudachitin treatment, suggesting a possible molecular mechanism underlying sudachitin-mediated improvement in glucose uptake. Transcription of the adiponectin gene in high-fat diet-fed mice treated with sudachitin showed a trend toward an increase that did not reach statistical significance, compared to the observation in vehicle-treated high-fat diet-fed mice. The mRNA level of PPARγ showed a trend towards an increase (1.5-fold) which was not statistically significant in the sudachitin-treated group compared with the vehicle-treated group. No significant differences in mRNA transcripts of adipocyte fatty acid-binding protein and CD36 were observed between the two treatment groups (Figure 5A). mRNA transcripts of uncoupling protein 1 and 3 (UCP1 and UCP3) were significantly increased in sudachitin-treated mice, which suggests that WAT gained a BAT-like phenotype, possibly resulting in increased thermogenesis.In the liver, we found that sudachitin decreased the levels of mRNA transcripts encoding FAS, ACC1 and ACC2, while the expression levels of DGAT1, DGAT2, and SREBP1, were not significantly different between vehicle- and sudachitin-treated mice fed a high-fat diet (Figure 5C). In addition, the expression levels of FDS, SS, HMG-R, and HMG-S were not affected by sudachitin (Figure 5C). The expression levels of MTTP and LDLR were not significantly different, although MTTP expression tended to be lower in the sudachitin-treated mice fed a high-fat diet as compared to the untreated high-fat diet-fed mice, although not significantly. There were no differences in the transcription of UCP2, ACOX, or PGC-1α between mice treated with sudachitin or vehicle (Figure 5C). However, transcription of the lipolytic gene HSL was increased in sudachitin-treated mice fed a high-fat diet, as was CPT1α, but there was no change in ATL (Figure 5C). The hepatic transcription of G6Pase and PEPCK, PPARγ, and adiponectin were not increased by sudachitin.


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 mRNA levels in white adipose tissue and liver. Gene transcription was normalized for 36B4 in subcutaneous white adipose tissue (A-B) or 18S in liver (C). Data are means ± standard deviation. *P < 0.05 vs the indicated groups. Closed bars: vehicle-treated, high-fat diet group; open bars: sudachitin-treated, high-fat diet group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Effects of sudachitin on mRNA levels in white adipose tissue and liver. Gene transcription was normalized for 36B4 in subcutaneous white adipose tissue (A-B) or 18S in liver (C). Data are means ± standard deviation. *P < 0.05 vs the indicated groups. Closed bars: vehicle-treated, high-fat diet group; open bars: sudachitin-treated, high-fat diet group.
Mentions: As shown in Figure 5A, GLUT4 mRNA levels were significantly increased by the sudachitin treatment, suggesting a possible molecular mechanism underlying sudachitin-mediated improvement in glucose uptake. Transcription of the adiponectin gene in high-fat diet-fed mice treated with sudachitin showed a trend toward an increase that did not reach statistical significance, compared to the observation in vehicle-treated high-fat diet-fed mice. The mRNA level of PPARγ showed a trend towards an increase (1.5-fold) which was not statistically significant in the sudachitin-treated group compared with the vehicle-treated group. No significant differences in mRNA transcripts of adipocyte fatty acid-binding protein and CD36 were observed between the two treatment groups (Figure 5A). mRNA transcripts of uncoupling protein 1 and 3 (UCP1 and UCP3) were significantly increased in sudachitin-treated mice, which suggests that WAT gained a BAT-like phenotype, possibly resulting in increased thermogenesis.In the liver, we found that sudachitin decreased the levels of mRNA transcripts encoding FAS, ACC1 and ACC2, while the expression levels of DGAT1, DGAT2, and SREBP1, were not significantly different between vehicle- and sudachitin-treated mice fed a high-fat diet (Figure 5C). In addition, the expression levels of FDS, SS, HMG-R, and HMG-S were not affected by sudachitin (Figure 5C). The expression levels of MTTP and LDLR were not significantly different, although MTTP expression tended to be lower in the sudachitin-treated mice fed a high-fat diet as compared to the untreated high-fat diet-fed mice, although not significantly. There were no differences in the transcription of UCP2, ACOX, or PGC-1α between mice treated with sudachitin or vehicle (Figure 5C). However, transcription of the lipolytic gene HSL was increased in sudachitin-treated mice fed a high-fat diet, as was CPT1α, but there was no change in ATL (Figure 5C). The hepatic transcription of G6Pase and PEPCK, PPARγ, and adiponectin were not increased by sudachitin.

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