Integration of Feeding Behaviour by the Liver Circadian Clock Reveals Network Dependency of Metabolic Rhythms [RNA-seq]

The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Due to lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we present a model in which the interaction between feeding and the liver clock can be isolated in vivo by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE) in otherwise clock-less mice. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal glucose homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism. To study how CEBPB affects circadian transcription we generated transient knock-down (KD) cells by using a siRNA targeting Cebpb. Cells were synchronized with dexamethasone and RNA extracted at specific circadian time points (CT12 and CT24). To study the muscle clock-liver connection, we collected serum from WT and muscle specific BMAL1 knock-out mice (mKO) at zeitgeber time (ZT16). Cultured primary hepatocytes were treated with the collected serum for 24 hours.