The core mechanism of the mammalian circadian clock and its link to energy metabolism. The cellular oscillator is composed of a positive limb (CLOCK and BMAL1) and a negative limb (CRYs and PERs). CLOCK and BMAL1 dimerize in the cytoplasm and translocate to the nucleus. The CLOCK:BMAL1 heterodimer then binds to enhancer (E-box) sequences located in the promoter region of Per and Cry genes, activating their transcription. After translation, PERs and CRYs undergo nuclear translocation and inhibit CLOCK:BMAL1, resulting in decreased transcription of their own genes. CLOCK:BMAL1 heterodimer also induces the transcription of Rev-erbα and Rorα. RORα and REV-ERBα regulate lipid metabolism and adipogenesis, and also participate in the regulation of Bmal1 expression. RORα stimulates and REV-ERBα inhibits Bmal1 transcription, acting through RORE. CLOCK:BMAL1 heterodimer also mediates the transcription of Pparα, a nuclear receptor involved in glucose and lipid metabolism. PPARα activates transcription of Rev-erba by binding to a peroxisome proliferator-response element (PPRE). PPARα also induces Bmal1 expression, acting through PPRE located in its promoter.
