Figure 1.

The circadian regulation of hepatic gluconeogenesis illustrates an example of bi-directional regulation between clock genes and metabolism. The HPA axis is entrained to the light/dark cycle, and NAD⁺ availability is entrained to feeding rhythms. NAMPT facilitates NAD⁺ salvage pathway. NAD⁺ co-activates SIRT1, which then activates PGC-1α. PGC-1α activated FOXO1 is necessary for transcription of Pck1 and G6pc genes, along with the cortisol-receptor complex. Cortisol bound to its receptor entrains the clock genes to the light/dark cycle. In summary, the transcription of gluconeogenic genes (Pck1/G6pc) is regulated by cortisol-receptor complex, clocks, and FOXO1.