Rev-erbα in the brain is essential for circadian food entrainment

Foraging is costly in terms of time and energy. An endogenous food-entrainable system allows anticipation of predictable changes of food resources in nature. Yet the molecular mechanism that controls food anticipation in mammals remains elusive. Here we report that deletion of the clock component Rev-erb alpha impairs food entrainment in mice. Rev-erb alpha global knockout (GKO) mice subjected to restricted feeding showed reduced elevations of locomotor activity and body temperature prior to mealtime, regardless of the lighting conditions. The failure to properly anticipate food arrival was accompanied by a lack of phase-adjustment to mealtime of the clock protein PERIOD2 in the cerebellum, and by diminished expression of phosphorylated ERK 1/2 (p-ERK) during mealtime in the mediobasal hypothalamus and cerebellum. Furthermore, brain-specific knockout (BKO) mice for Rev-erb alpha display a defective suprachiasmatic clock, as evidenced by blunted daily activity under a light-dark cycle, altered free-running rhythm in constant darkness and impaired clock gene expression. Notably, brain deletion of Rev-erb alpha totally prevented food-anticipatory behaviour and thermogenesis. In response to restricted feeding, brain deletion of Rev-erb alpha impaired changes in clock gene expression in the hippocampus and cerebellum, but not in the liver. Our findings indicate that Rev-erb alpha is required for neural network-based prediction of food availability.