A Minimal Circadian Clock Network for Glucose Tolerance in Mice
Physiology is regulated by interconnected cell and tissue circadian clocks.  Disruption of the rhythms generated by this interconnectedness is associated with  metabolic disease. Here we tested the interactions between clocks in two critical  components of organismal metabolism – liver and skeletal muscle – by rescuing  clock function either in each organ separately, or in both organs simultaneously,  in otherwise clock-less mice. Experiments revealed that individual clocks are  partially sufficient for tissue glucose metabolism, yet the connections between  both tissue clocks coupled with daily feeding rhythms maximizes systemic  glucose tolerance. This synergy relies in part on local transcriptional control of  the glucose machinery, feeding-responsive signals such as insulin, and metabolic  cycles that connect the muscle and liver. We posit that spatiotemporal  mechanisms of muscle and liver play an essential role in the maintenance of  systemic glucose homeostasis, and that disrupting this diurnal coordination can  contribute to the metabolic disease. Overall design: Gastocnemius muscle and livers were harvested from WT, Bmal1-KO, Liver-RE, Muscle-RE and Liver+Muscle-RE mice after 2 weeks of food access only during the 12 hour dark phase. Bulk RNA-seq was performed on harvested tissues. ZT refers to time in hours since the start of the 12 hour light dark cycle.