Most cells in the body contain a cell autonomous molecular clock, but the requirement of peripheral clocks for circadian rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERB alpha and β in adult mouse hepatocytes disrupted circadian rhythmicity of many liver genes, as expected, but also led to maintained and even gained rhythmicity of other genes without altering feeding behavior. The loss of REV-ERBs from hepatocytes led to an exaggerated circadian rhythm of de novo lipogenesis. Liver function is also influenced by non-hepatocytic cells, and remarkably the loss of REV-ERBs in hepatocytes remodeled the circadian transcriptomes and metabolomes of multiple cell types within the liver, indicating that hepatocytes communicated time signals to non-hepatocytic cells. Finally, alteration of food availability demonstrated strong interdependence of the cell-autonomous hepatocyte clock mechanism and non-cell-autonomous environmental change. Together these studies reveal previously unsuspected roles of the hepatocyte clock in the physiological coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.
D. Guan: None. M.A. Lazar: Board Member; Self; Pfizer Inc. Consultant; Self; Calico, Madrigal Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation.
National Institute of Diabetes and Digestive and Kidney Diseases (F32DK116519)