PER1 Phosphorylation Specifies Feeding Rhythm in Mice

Organization of circadian behavior, physiology, and metabolism is important for human health. An S662G mutation in hPER2 has been linked to familial advanced sleep-phase syndrome (FASPS). Although the paralogous phosphorylation site S714 in PER1 is conserved in mice, its specific function in circadian organization remains unknown. Here, we find that the PER1S714G mutation accelerates the molecular feedback loop. Furthermore, hPER1S714G mice, but not hPER2S662G mice, exhibit peak time of food intake that is several hours before daily energy expenditure peaks. Both the advanced feeding behavior and the accelerated clock disrupt the phase of expression of several key metabolic regulators in the liver and adipose tissue. Consequently, hPER1S714G mice rapidly develop obesity on a high-fat diet. Our studies demonstrate that PER1 and PER2 are linked to different downstream pathways and that PER1 maintains coherence between the circadian clock and energy metabolism. [Display omitted] [Display omitted] •S714G mutation in PER1 causes internal clock misalignment•S714G mutation in PER1 is associated with feeding rhythms•PER1S714G mice rapidly develop obesity•PER1 is an important regulator of interactions between clock and energy metabolism Loss-of-function mutations have revealed how clock components generate 24 hr rhythms. However, the mechanisms that ensure timing of sleep and metabolism in a 24 hr day are unclear. A missense mutation at a phosphorylation site in the clock component Period2 advances sleep onset and causes advanced-phase syndrome. In this study, Liu et al. find that an equivalent mutation in human Period1 mistimes feeding and predisposes to obesity in mice. Hence, posttranslational modifications of clock components orchestrate timing of behavior, metabolism, and physiology.