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

Abstract

BackgroundObesity 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.MethodsC57BL/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.ResultsSudachitin 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.ConclusionsSudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders.

Effect of bergamot on lipid profile in humans: A systematic review

“…Some authors have also proposed different mechanisms that may concur in lipid homeostasis regulation by flavonoids. These included the activation of situin-1, which in turns activate adenosine monophosphate-activated protein kinase (AMPK)-a by increasing fatty acid oxidation and decreasing VLDL synthesis through of hepatocyte nuclear factor 4 (HNF4) inhibition, sterol regulatory element-binding protein 1 (SREBP-1) regulation (Tsutsumi et al 2014;Bruckbauer and Zemel 2014;Chang et al 2013;Quesada et al 2009) and the inhibition of the pancreatic cholesterol ester hydrolase and Acyl-CoA cholesterol acyltransferase, which increase the cholesterol fecal excretion (Musolino et al 2017). Despite this is the most probable mechanism like bergamot, there are other mechanisms that have been proposed to be responsible for lipid-lowering effects of bergamot.…”

Methanol extraction fraction from Citrus Sudachi peel exerts lipid reducing effects in cultured cells

“…It was reported that obesity could be treated by promoting the activity of native UCP. Tsutsumi also reported that UCP2 gene expression was significantly increased in skeletal muscle of mice which improved glucose and lipid metabolism (9). Molecular mechanisms how M-F4 exerts the lipid-lowering effects we propose is summarized in Fig.…”

Extracts of <i>citrus Sudachi</i> peel attenuate body weight gain in C57BL/6 mice fed a high-fat diet

“…This function is effective for preventing obesity in an animal model. Indeed, treatment with sudachitin at 5 mg/kg body weight improved the serum lipid profile and reduced body weight in mice fed a high-fat diet (4). In this study, we examined effect of SPE on body weight in mice fed a high-fat and found that SPE attenuate body weight gain.…”

“…Fat weight including visceral and subcutaneous fat and serum levels of tryglyceride and cholesterol were also reduced in the sudachitin-treated group. We also examined the mechanism and found that sudachitin increases Sirt1, PGC1-α and UCP-1 gene expression, resulting in enhancement of energy expenditure (4).…”