Feeding regime synchronizes circadian clock in choroid plexus - insight into a complex mechanism

TL;DR

This study shows that feeding schedules can reset the circadian clock in the choroid plexus, aligning it with meal times rather than the day-night cycle.

Contribution

The study identifies feeding-induced signals like insulin, glucose, and temperature as key factors in resetting the choroid plexus clock.

Findings

Reverse restricted feeding shifts the circadian clock in the choroid plexus of both the fourth and lateral ventricles.

Glucose's effect on the clock is partially mediated by O-GlcNAcylation, as shown by partial inhibition with OSMI-1.

The fourth ventricle choroid plexus responds more strongly to feeding cues than the lateral ventricle.

Abstract

The circadian clock in choroid plexus (ChP) controls processes involved in its physiological functions, but the signals that synchronize the clock have been sparsely studied. We found that the ChP clock in the fourthventricle (4V) is more robust than that in the lateral ventricle (LV) and investigated whether both clocks use information about mealtime as a signal to synchronize with the current activity state. Exposure of mPer2Luc mice to a 10-day reverse restricted feeding (rRF) protocol, in which food was provided for 6 h during daytime, advanced the phase of the ChP clock in 4V and LV, as evidenced by shifted (1) PER2-driven bioluminescence rhythms of ChP explants ex vivo and (2) daily profiles in clock gene expression in both ChP tissues in vivo. In contrast, clocks in other brain regions (DMH, ARC, LHb) of the same mice did not shift. The 4V ChP responded more strongly than the LV ChP to rRF by modulating the expression of genes to ensure a decrease in resistance to cerebrospinal fluid drainage and increase the secretory capacity of ChP cells. Mechanistically, rRF affects the ChP clock through food-induced increases in insulin, glucose and temperature levels, as in vitro all three signals significantly shifted the clocks in both ChP tissues, similar to rRF. The effect of glucose was partially blocked by OSMI-1, suggesting involvement of O-linked N-acetylglucosamine posttranslational modification. We identified mechanisms that can signal to the brain the time of feeding and the associated activity state via resetting of the ChP clock.

Summary of results. Reverse restricted feeding (rRF), which shifts the timing of food intake into the daytime, leads to a corresponding shift in the rise of insulin and glucose levels as well as activity-related body temperature. As a result, the clocks in the choroid plexus of the fourth ventricle (4V ChP) and the lateral ventricle (LV ChP) shift accordingly (the effect of glucose is partly mediated via O-GlcNAcylation). In this way, clock-controlled ChP function follows the timing of food rather than solar cycle.

The online version contains supplementary material available at 10.1007/s00018-025-05798-3.

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