The Polymethoxyflavone Sudachitin Modulates the Circadian Clock and Improves Liver Physiology

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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 revealed 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, we showed that Sudachitin modulated circadian amplitude and period of Bmal1 promoter-driven reporter rhythms, and real-time qPCR analysis showed that Sudachitin altered expression of core clock genes, notably Bmal1, at both transcript and protein levels. Mass-spec analysis revealed systemic exposure in vivo. In mice fed with high-fat diet with or without Sudachitin, we observed 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 revealed prevalent diurnal alteration in both gene expression and metabolite accumulation. Conclusion: Our study elucidates Sudachitin as a new clock-modulating PMF with beneficial effects to to improve diurnal metabolic homeostasis and liver physiology, suggesting the circadian clock as a fundamental mechanism to safeguard physiological well-being.

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