Whole-body deletion of RORα in mice leads to time-dependent disruption in hepatic triglyceride synthesis.
Hepatic triglyceride synthesis is reduced during the light phase in RORα-knockout mice.
Altered transcriptional regulation of key metabolic genes, including and , is observed.
Increased transcription of Srebp1c at night does not result in expected lipid synthesis due to phase-shifted Insig expression.
The rhythmic expression of core clock genes is attenuated, with Reverbα showing phase shifts.
Pharmacological inhibition of RORα produces similar metabolic effects as the genetic deletion in mice.
Simplified
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 and . 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.
Key numbers
28–30%
Decrease in hepatic TG synthesis
Observed in WT mice treated with SR3335 at ZT0.
1.3-fold
Increase in glucose neo-production
Measured in liver explants from WT mice treated with SR1078 at ZT10.
1.5-fold
Increase in glucose incorporation into TG
Observed in liver explants from WT mice treated with SR1078.
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