RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis
Abstract 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 an...
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Nature Portfolio
2025-03-01
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| Online Access: | https://doi.org/10.1038/s41598-025-95228-y |
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| author | Chloé Monnier Munkhzul Ganbold Martine Auclair Natacha Roblot Andréas Barnabé Boutin Paul Ketil Boutin Bruno Fève Bénédicte Antoine |
| author_facet | Chloé Monnier Munkhzul Ganbold Martine Auclair Natacha Roblot Andréas Barnabé Boutin Paul Ketil Boutin Bruno Fève Bénédicte Antoine |
| author_sort | Chloé Monnier |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-2fb0412efaeb48cd82a28ce1cecdfd8c2025-08-20T03:41:14ZengNature PortfolioScientific Reports2045-23222025-03-0115111410.1038/s41598-025-95228-yRORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesisChloé Monnier0Munkhzul Ganbold1Martine Auclair2Natacha Roblot3Andréas Barnabé Boutin4Paul Ketil Boutin5Bruno Fève6Bénédicte Antoine7UMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermUMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermUMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermUMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermUMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermUMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermUMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermUMR_S938, Centre de Recherche Saint-Antoine, IHU ICAN, Faculté de Médecine Site Saint-Antoine, Sorbonne Université-InsermAbstract 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.https://doi.org/10.1038/s41598-025-95228-yLiverLipid synthesisRORαCircadian rhythmsGluconeogenesisStaggerer |
| spellingShingle | Chloé Monnier Munkhzul Ganbold Martine Auclair Natacha Roblot Andréas Barnabé Boutin Paul Ketil Boutin Bruno Fève Bénédicte Antoine RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis Scientific Reports Liver Lipid synthesis RORα Circadian rhythms Gluconeogenesis Staggerer |
| title | RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis |
| title_full | RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis |
| title_fullStr | RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis |
| title_full_unstemmed | RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis |
| title_short | RORα fine-tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis |
| title_sort | rorα fine tunes the circadian control of hepatic triglyceride synthesis and gluconeogenesis |
| topic | Liver Lipid synthesis RORα Circadian rhythms Gluconeogenesis Staggerer |
| url | https://doi.org/10.1038/s41598-025-95228-y |
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