Mathematical models converge on PGC1α as the key metabolic integrator of SIRT1 and AMPK regulation of the circadian clock

How the mammalian circadian clock interacts with metabolism and its possible implications in metabolic diseases are actively studied. In PNAS, Foteinou et al. (1) propose a mathematical model of the circadian clock that incorporates the metabolic sensor SIRT1 and validate it with cell experiments. Their findings shed light on conflicting reports by Asher et al. (2) and Nakahata et al. (3) about the effect of SIRT1 deficiency on clock function and SIRT1 targets. The authors conclude that SIRT1 acts on the clock not only via the well-known clock protein PER2, but also through PGC-1α, a transcriptional co-activator of the BMAL1 clock gene with key metabolic functions. Interestingly, the Foteinou model is comparable to the model designed by Woller et al. (4) to understand the mechanisms of liver clock disruption observed upon high-fat diet (HFD) consumption. The two models describe the dynamics of the same molecular network, except that Woller et al. additionally consider clock regulation by the energy sensor AMPK. Remarkably, both models point to a key role of PGC-1α in the circadian clock from different perspectives. The Woller model takes into account the NAMPT-NAD+-SIRT1-PGC1α-ROR-BMAL1 metabolic loop and show its requirement to reproduce the dampened oscillations in clock gene expression observed by Hatori et al. (5) and Eckel-Mahan et al. (6) upon HFD feeding, a condition mimicked by altered AMPK activity. On the other hand, Foteinou et al. (1) report that inclusion of PGC-1α in their model is needed to reproduce correctly the altered reporter expression levels upon combined SIRT1 and BMAL1 silencing. These findings confirm the role of PGC-1α linking SIRT1 and AMPK activities: PGC-1α needs to be phosphorylated by AMPK before it can be deacetylated by SIRT1 (7). The key role of PGC-1α,