Recent results have established an interdependence between SIRT1 and the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK), which contributes to the metabolic adaptation to fasting and exercise in skeletal muscle (Canto et al. 2010). Importantly, AMPK was found to play a role in the control of circadian rhythms by phosphorylating and inducing the destabilizion of CRY1 in a cyclic manner (Lamia et al. 2009). Stimulation of AMPK signaling alters circadian rhythms, and mice in which the AMPK pathway is genetically disrupted show alterations in peripheral clocks. Thus, it appears that phosphorylation by AMPK enables CRY1 to transduce nutrient signals to circadian clocks in mammalian peripheral organs. How SIRT1, and possibly NAD+ oscillations, may be involved in this control system is as yet unclear.

The involvement of SIRT1 in circadian regulation demonstrated a direct link between cyclic rhythms and energy metabolism in the cell (Asher et al. 2008; Nakahata et al. 2008). Yet, analyses along the circadian cycle in various cell types demonstrated that the expression levels of the SIRT1 gene and protein are noncyclic (Fig. 2) (Nakahata et al. 2008; Ramsey et al. 2009). On the contrary, the HDAC activity of the enzyme is circadian, indicating that some other sort of regulation—unrelated to protein levels—had to intervene to regulate SIRT1 function (Fig. 2). Thus the question we had was, How can two enzymes that are mostly expressed in a nonoscillatory manner lead to circadian acetylation of K9/K14 in histone H3 and K537 in BMAL1? (Fig. 4). This apparent discrepancy was solved by subsequent studies that revealed that NAD+ levels oscillate in a circadian fashion in all cell types analyzed and that it is through the cyclic availability of its own coenzyme that SIRT1 HDAC activity is circadian (Nakahata et al. 2009; Ramsey et al. 2009). The circadian regulation of NAD+ synthesis is itself conceptually remarkable because it links the transcriptional feedback loop of the circadian clock to an enzymatic pathway.