The Polymethoxyflavone Sudachitin Modulates the Circadian Clock and Improves Liver Physiology

Abstract

Scope Polymethoxylated flavones (PMFs) are a group of natural compounds known to display a wide array of beneficial effects to promote physiological fitness. Recent studies reveal circadian clocks as an important cellular mechanism mediating preventive efficacy of the major PMF Nobiletin against metabolic disorders. Sudachitin is a PMF enriched in Citrus sudachi, and its functions and mechanism of action are poorly understood. Methods and results Using circadian reporter cells, it shows that Sudachitin modulates circadian amplitude and period of Bmal1 promoter‐driven reporter rhythms, and real‐time qPCR analysis shows that Sudachitin alters expression of core clock genes, notably Bmal1, at both transcript and protein levels. Mass‐spec analysis reveals systemic exposure in vivo. In mice fed with high‐fat diet with or without Sudachitin, it observes increased nighttime activity and daytime sleep, accompanied by significant metabolic improvements in a circadian time‐dependent manner, including respiratory quotient, blood lipid and glucose profiles, and liver physiology. Focusing on liver, RNA‐sequencing and metabolomic analyses reveal prevalent diurnal alteration in both gene expression and metabolite accumulation. Conclusion This study elucidates Sudachitin as a new clock‐modulating PMF with beneficial effects to improve diurnal metabolic homeostasis and liver physiology, suggesting the circadian clock as a fundamental mechanism to safeguard physiological well‐being.

Effects of (Poly)phenols on Circadian Clock Gene–Mediated Metabolic Homeostasis in Cultured Mammalian Cells: A Scoping Review

“…The studies included in this review were published from 2008 to 2024, with the majority published after 2016, reflecting the growing scientific interest in (poly)phenols and circadian biology. Table 2 [ [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] , [89] , [90] , [91] , [92] , [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] , [106] , [107] , [108] , [109] ] summarizes the main characteristics and outcomes of the included studies.…”

Sudachitin and Nobiletin Stimulate Lipolysis via Activation of the cAMP/PKA/HSL Pathway in 3T3-L1 Adipocytes

“…Intake of citrus peel polymethoxyflavones, such as sudachitin and nobiletin, prevents obesity in humans and rodents [25][26][27]40]. Nobiletin is known to promote lipolysis in adipocytes [14].…”

“…Sudachitin exerts anti-obesogenic effects in rodents and humans [25][26][27]. A previous study demonstrated that sudachitin suppresses HFD-induced obesity by stimulating mitochondrial biogenesis in myocytes.…”

“…Recently, Shikishima et al, reported that sudachitin-containing sudachi peel extracts decrease the ratio of abdominal fat to subcutaneous fat and modestly decrease abdominal circumference [25]. Sudachitin improved hyperlipidemia and hyperglycemia in mice that were fed a HFD [26]. It is assumed that the improvement in metabolism is due to the increase in energy expenditure, as sudachitin increases mitochondrial biogenesis in murine skeletal muscles [27].…”

Phytochemicals and Vitamin D for a Healthy Life and Prevention of Diseases

“…It is also found in some citrus fruits, including Japanese mandarins, grapefruits, lemons (Citrus limon), and limes (Citrus aurantiifolia), as well as buckwheat (Fagopyrum esculentum), and is used as a vascular protection medication in many countries [26]. Recently, Sudachitin, which is present in Sudachi (Citrus Sudachi), has been shown to regulate circadian rhythm and suppress the accumulation of fat in the liver [27].…”