Review Volume 2, Issue 1 pp 7—27

Figure 2. The core mechanism of the mammalian circadian clock and its link to energy metabolism. (A) High NAD(P)H levels promote CLOCK:BMAL1 binding to E-box sequences leading to the acetylation of BMAL1 and expression of Pers, Crys, and other clock-controlled genes. The negative feedback loop, PERs:CRYs, binds to CLOCK:BMAL1 and consequently PERs are acetylated. Activated AMPK leads to a rise in NAD+ levels, phosphorylation of CRYs, and phosphorylation of CKI?, which then phosphorylates the PERs. As a result of increased NAD+ levels, SIRT1 deacetylates PERs and BMAL1. This and the destabilization of phosphorylated PERs and CRYs relieves PERs:CRYs repression and another cycle starts. (B) Expression of Bmal1 and Rev-erbα genes are controlled by PPARα and binding of RORs to RORE sequences. RORs need a co-activator, PGC-1α, which is phosphorylated by activated AMPK. In parallel, AMPK activation leads to an increase in NAD+ levels, which, in turn activate SIRT1. SIRT1 activation leads to PGC-1α deacetylation and activation. Acetyl adenosine diphosphate ribose (Ac-ADP-r) and nicotinamide (NAM) are released after deacetylation by SIRT1.