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

Metabolic homeostasis is regulated by circadian clocks. Disruption to our circadian clocks, by lifestyle behaviors such as timing of eating and sleeping, has been linked to increased rates of metabolic disorders. There is now considerable evidence that selected dietary (poly)phenols, including flavonoids, phenolic acids and tannins, may modulate both metabolic and circadian processes. This review evaluates the effects of (poly)phenols on circadian clock genes and linked metabolic homeostasis in vitro, and potential mechanisms of action, by critically evaluating the literature on mammalian cells. A systematic search was conducted to ensure full coverage of the literature, and identified 43 relevant studies addressing the effects of (poly)phenols on cellular circadian processes. Nobiletin and tangeretin, found in citrus, (-)-epigallocatechin-3-gallate from green tea, urolithin A, a gut microbial metabolite from ellagitannins in fruit, curcumin, bavachalcone, cinnamic acid and resveratrol at low micromolar concentrations all affect circadian molecular processes in multiple types of synchronized cells. Nobiletin emerges as a putative Retinoic acid-related Orphan Receptor (RORα/γ) agonist, leading to induction of the circadian regulator Brain and Muscle ARNT-Like 1 (BMAL1), and increased Period Circadian Regulator 2 (PER2) amplitude and period. These effects are clear despite substantial variations in the protocols employed, and this review suggests a methodological framework to help future study design in this emerging area of research.