Monnier Chloé, Ganbold Munkhzul, Auclair Martine, Roblot Natacha, Boutin Andréas Barnabé, Boutin Paul Ketil, Fève Bruno, Antoine Bénédicte
UMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-Inserm, 27 Rue Chaligny, 75012, Paris, France.
APHP, Department of Endocrinology and CRMR PRISIS, Saint-Antoine Hospital, Paris, France.
Sci Rep. 2025 Mar 26;15(1):10464. doi: 10.1038/s41598-025-95228-y.
Circadian rhythms play a fundamental role in hepatic metabolism, orchestrating lipid synthesis and glucose homeostasis. RORα, a nuclear receptor involved in circadian regulation, has been implicated in fine-tuning these metabolic processes. We previously showed a therapeutic potential of antagonizing RORα to reduce body fat in mice. Our current aim is to investigate the impact of the whole-body RORα deletion on hepatic lipid metabolism over a complete circadian cycle. Using RORα-knockout (staggerer) mice, this study reveals a time-dependent disruption in hepatic triglyceride synthesis, with reduced lipogenesis during the light-phase and altered transcriptional regulation of key metabolic genes, including Srebp1c and Insigs. Despite increased Srebp1c transcription at night, the anticipated rise in lipid synthesis was prevented by phase-shifted Insig expression, modulating precursor maturation. Moreover, core clock genes rhythmic expression was attenuated and phase-shifted for Reverbα. Pharmacological inhibition of RORα using an inverse agonist (SR3335) mirrored the metabolic effects observed in staggerer mice, further supporting the role of RORα as a crucial regulator of lipid and glucose homeostasis in mice fed a chow diet. These findings highlight the intricate interaction between the circadian clock and hepatic metabolism, situating RORα as a promising target to prevent metabolic disorders such as obesity and dyslipidemia.
昼夜节律在肝脏代谢中起着基础性作用，协调脂质合成和葡萄糖稳态。RORα是一种参与昼夜节律调节的核受体，已被证明在微调这些代谢过程中发挥作用。我们之前表明，拮抗RORα具有降低小鼠体脂的治疗潜力。我们目前的目标是研究在一个完整的昼夜周期内全身RORα缺失对肝脏脂质代谢的影响。利用RORα基因敲除（蹒跚）小鼠，本研究揭示了肝脏甘油三酯合成的时间依赖性破坏，在光照期脂肪生成减少，关键代谢基因（包括Srebp1c和Insigs）的转录调控发生改变。尽管夜间Srebp1c转录增加，但Insig表达的相位变化阻止了预期的脂质合成增加，从而调节前体成熟。此外，核心生物钟基因的节律性表达减弱，Reverbα发生相位变化。使用反向激动剂（SR3335）对RORα进行药理学抑制反映了在蹒跚小鼠中观察到的代谢效应，进一步支持了RORα作为正常饮食喂养小鼠脂质和葡萄糖稳态关键调节因子的作用。这些发现突出了昼夜节律钟与肝脏代谢之间的复杂相互作用，将RORα定位为预防肥胖和血脂异常等代谢紊乱的有前景的靶点。
