Expression of the clock gene Rev‐erbα in the brain controls the circadian organisation of food intake and locomotor activity, but not daily variations of energy metabolism

Abstract

The nuclear receptor REV-ERBα is part of the molecular clock mechanism and is considered to be involved in a variety of biological processes within metabolically active peripheral tissues as well. To investigate whether Rev-erbα (also known as Nr1d1) in the brain plays a role in the daily variations of energy metabolism, feeding behaviour and the sleep-wake cycle, we studied mice with global (GKO) or brain (BKO) deletion of Rev-erbα. Mice were studied both in a light/dark cycle and in constant darkness, and then 24-hour variations of Respiratory quotient (RQ) and energy expenditure, as well as the temporal patterns of rest-activity and feeding behaviour, were recorded. The RQ increase of GKO mice was not detected in BKO animals, indicating a peripheral origin for this metabolic alteration. Arrhythmic patterns of locomotor activity were only found in BKO mice. By contrast, the circadian rhythm of food intake was lost both in GKO and BKO mice, mostly by increasing the number of daytime meals. These changes in the circadian pattern of feeding behaviour were, to some extent, correlated with a loss of rhythmicity of hypothalamic Hcrt (also named Orx) mRNA levels. Taken together, these findings highlight that Rev-erbα in the brain is involved in the temporal partitioning of feeding and sleep, whereas its effects on energy metabolism are mainly exerted through its peripheral expression. K E Y W O R D Scircadian rhythm, clock gene, energy expenditure, feeding behaviour, hypothalamus, Nr1d1 | INTRODUCTIONDaily variations of behavioural and metabolic processes, such as the sleep-wake cycle and feeding-fasting rhythm, are controlled by a network of circadian clocks in the brain and peripheral tissues. In mammals, the main circadian clock is located in the suprachiasmatic nuclei of the hypothalamus, and is mostly reset by light perceived by the retina. 1,2Secondary clocks present in other cerebral regions and peripheral organs (eg, liver, muscle and pancreas) are adjusted in phase by the suprachiasmatic clock via the autonomic nervous system and endocrine signals. 3,4The secondary clocks can also be shifted by behavioural factors, such as food intake. 5,6 The molecular clockwork is based on autoregulatory transcriptional/translational feedback loops that generate rhythmic transcriptional activity with an approximately 24-hour period. In this network, two transcriptional activators, CLOCK and BMAL1, stimulate the expression of Period (Per1-3) and Cryptochrome (Cry1,2) genes, whose proteins in turn can repress the CLOCK-BMAL1 transactivation. 7 In addition to these main components, the nuclear receptors Ror(α,β,γ) and -erb(α,β) compete to activate and repress, respectively, the transcription of Bmal1 and Clock, thereby reinforcing the robustness of circadian oscillations. [8][9][10] The amplitude of the circadian oscillations is further enhanced by targeted degradation of REV-ERBα. Besides its role in the internal timing system, REV-ERBα is also in- Feeding behaviour is strongly organised in time at both ultradian (ie, meal)...

Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

“…One candidate form of metabolic perturbation is disordered feeding behavior. Both mice with brain-targeted Reverbα deletion and global Reverbα −/− mice exhibit abnormal rhythms of feeding activity (increased daytime feeding) (38). Indeed, on closely tracking the food intake of Reverbα −/− mice and comparing it to WT controls, we observed far greater variability over the course of the day, while total intake remained comparable (SI Appendix, Fig.…”

The Suprachiasmatic Nucleus Regulates Anxiety-Like Behavior in Mice

“…The period of activity rhythms was determined by applying a least-squares fit to the onset measures. Homecage activity amplitude was quantified using a least-squares fit cosinor analysis similar to cosinor analyses used in previous studies to quantify changes in mouse activity or human actigraphy rhythms ( Park et al, 2012 ; Hopkins et al, 2017 ; Palmisano et al, 2017 ; Musiek et al, 2018 ; Sen et al, 2018 ). For stimulation at CT21, the period of homecage activity over the analysis range was used for the cosinor fit.…”

Photoperiod Manipulation Reveals a Light-Driven Component to Daily Patterns of Ventilation in Male C57Bl/6J Mice

“…Therefore, shortened photoperiods may promote a switch toward an OSA phenotype, and potentially explain why OSA symptoms are more severe in the winter (Cassol et al, 2012). One explanation for the decrease in RER under L5 may be that altering photoperiod drives changes in peripheral expression patterns of clock genes, which can have direct effects on glucose and lipid metabolism (Sosniyenko et al, 2010; Sen et al, 2018; Yin et al, 2020). However, further studies are needed to understand the contributions of photoperiodic changes in clock gene expression to metabolic and ventilatory patterns.…”