Frequent Shifts During Chronic Jet Lag Uncouple Liver Rhythms From the Light Cycle in Male Mice

Circadian disruption is pervasive in modern society and associated with increased risk of disease. Chronic jet lag paradigms are popular experimental tools aiming to emulate human circadian disruption experienced during rotating and night shift work. Chronic jet lag induces metabolic phenotypes tied to liver and systemic functions, yet lack of a clear definition for how rhythmic physiology is impaired under these conditions hinders the ability to identify the underlying molecular mechanisms. Here, we compared 2 common chronic jet lag paradigms and found that neither induced arrythmicity of the liver and each had distinct effects on rhythmicity. Instead, more frequent 8-h forward shifts of the light schedule induced more severe misalignment and non-fasted hyperglycemia. Every other day shifts eventually uncoupled behavioral and hepatic rhythms from the light cycle, reminiscent of free-running conditions. These results point to misalignment, not arrhythmicity, as the initial disturbance tied to metabolic dysfunction in environmental circadian disruption and highlight considerations for the interpretation and design of chronic jet lag studies.