CLOCK and metabolic disease: 18-22 These form a well-characterized transcriptional-translational feedback loop to maintain cyclical expression (Figure 1A).23 Genetic or environmental disruption of the core clock induces metabolic disease in mice and humans, while obesity alters rhythmic circadian gene expression.24-27 Recent data, however, suggest that the therapeutic metabolic response to time-restricted feeding is largely independent of the core clock.28 Thus, how and whether such signals interact to dictate fuel selection and survival remains incompletely addressed.