The liver clock drives circadian rhythms in white adipose tissue [WT_LKO]

Circadian rhythms are integral to maintaining metabolic health by temporally coordinating metabolic functions across tissues. However, the mechanisms underlying circadian cross-tissue coordination remain poorly understood. In this study, we uncover a central role for the liver clock in regulating circadian rhythms in white adipose tissue (WAT). Using a liver-specific Bmal1 knockout mouse model, we show that hepatic circadian control is crucial for lipid metabolism in WAT. In addition, by utilizing a model where functional clocks are restricted to the liver, we demonstrate that the liver clock alone drives circadian gene expression in WAT, including Cebpa, a key regulator of adipogenesis. Mechanistically, we show that circadian liver-to-WAT communication is mediated through secreted proteins, including the adaptor protein 14-3-3η (Ywhah). The clinical relevance of these findings is supported by human cohort data, which correlate liver YWHAH expression with lipid metabolic pathways in WAT and cardiometabolic risk factors. These findings provide a mechanistic framework for how the liver clock coordinates WAT physiology and highlights its central role in cardiometabolic health, offering potential insights for targeted circadian-based therapies for metabolic disorders. Bulk SmartSeq3 from epidydemal white adipose tissue from male wild-type, and Liver-specific Bmal1-KO mice.