Vlassakev Ivan, Savva Christina, Renzi Gianluca, Ilamathi Hema S, Mamand Doste R, Smith Jacob G, Greco Carolina M, Litwin Christopher, Zhang Qing, Velez Leandro, Ma Angela, Bergo Martin O, Wiklander Oscar P B, Muñoz-Cánovez Pura, Mejhert Niklas, Seldin Marcus, Björkegren Johan L M, Sassone-Corsi Paolo, Koronowski Kevin B, Benitah Salvador Aznar, Petrus Paul
Department of Physiology and Pharmacology, C3, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Medicine (H7), Karolinska Institutet, Stockholm 141 86, Sweden.
Department of Medicine (H7), Karolinska Institutet, Stockholm 141 86, Sweden.
Mol Metab. 2025 Nov;101:102249. doi: 10.1016/j.molmet.2025.102249. Epub 2025 Sep 12.
Circadian rhythms are integral to maintaining metabolic health by temporally coordinating physiology 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 hepatocyte-specific Bmal1 knockout mouse model, we show that hepatic circadian control modulates lipid metabolism in WAT. In addition, by utilizing a model where functional clocks are restricted to the hepatocytes, we demonstrate that the liver clock alone integrates feeding cues to modulate circadian gene expression in WAT, including Cebpa, a key regulator of adipogenesis. We show that the hepatocyte clock regulates adipocyte Cebpa rhythmicity through secreted proteins. Further investigation identified one of the contributing mediators to be the adaptor protein 14-3-3η (Ywhah). The clinical relevance of the liver clock for systemic metabolic function is supported by human cohort data, which revealed a gene regulatory network, consisting of several clock-controlled liver genes, linked to cardiometabolic risk. These findings provide evidence for how the hepatocyte clock coordinates WAT physiology and highlights the core clock system as a potential therapeutic target to improve cardiometabolic health.
昼夜节律对于通过跨组织的时间协调生理功能来维持代谢健康至关重要。然而，昼夜跨组织协调的潜在机制仍知之甚少。在本研究中，我们揭示了肝脏生物钟在调节白色脂肪组织（WAT）昼夜节律中的核心作用。使用肝细胞特异性Bmal1基因敲除小鼠模型，我们表明肝脏昼夜节律控制调节WAT中的脂质代谢。此外，通过利用功能生物钟仅限于肝细胞的模型，我们证明仅肝脏生物钟就能整合进食信号来调节WAT中的昼夜节律基因表达，包括脂肪生成的关键调节因子Cebpa。我们表明肝细胞生物钟通过分泌蛋白调节脂肪细胞Cebpa的节律性。进一步研究确定其中一个促成介质是衔接蛋白14-3-3η（Ywhah）。人类队列数据支持了肝脏生物钟对全身代谢功能的临床相关性，该数据揭示了一个由几个生物钟控制的肝脏基因组成的基因调控网络，与心脏代谢风险相关。这些发现为肝细胞生物钟如何协调WAT生理功能提供了证据，并突出了核心生物钟系统作为改善心脏代谢健康的潜在治疗靶点。
