Is Vitamin D Signaling Regulated by and Does It Regulate Circadian Rhythms?

Since recent reports have indicated that vitamin D3 (D3) can affect sleep behavior, we asked the question of whether activation of D3 is regulated by the circadian clock and whether active forms of vitamin D3 regulate its molecular elements. While current evidence does not support circadian regulation of 25(OH)D3 and 1,25(OH)₂D3 production, there is experimental and molecular evidence that the circadian network may regulate CYP11A1 activity and by inference, the production of downstream D3-hydroxyderivatives. D3-hydroxyderivatives act as inverse agonists on RORα and γ, and as agonists on AhR, while molecular modeling indicated that D3-hydroxyderivatives can also act on RORβ and REV-ERBs. RORs and REV-ERBs regulate the transcription of several clock genes by binding ROR responsive elements (ROREs) in their promoter region. These data raise the concept that D3-hydroxyderivatives may directly regulate circadian clock genes via these receptors. Finally, literature data suggest that D3-hydroxyderivatives can affect the circadian clock indirectly via changes in systemic levels of melatonin. While these hypotheses remain to be experimentally validated, they open exciting areas of research on UVB regulation of the circadian system and possible circannual/seasonal rhythms through the generation of D3, its photoderivatives, or its hydroxylated metabolites. An open question remains whether such UVB-induced regulatory mechanisms are conserved through the animal and plant kingdoms. In summary, we propose that vitamin D3 signaling can both be regulated by the circadian network and that it can directly regulate the molecular clock through action on RORα/β/γ, REV-ERBα/β or AhR.