Ultradian feeding in mice not only affects the peripheral clock in the liver, but also the master clock in the brain

ABSTRACT

Restricted feeding during the resting period causes pronounced shifts in a number of peripheral clocks, but not the central clock in the suprachiasmatic nucleus (SCN). By contrast, daily caloric restriction impacts also the light-entrained SCN clock, as indicated by shifted oscillations of clock (PER1) and clock-controlled (vasopressin) proteins. To determine if these SCN changes are due to the metabolic or timing cues of the restricted feeding, mice were challenged with an ultradian 6-meals schedule (1 food access every 4 h) to abolish the daily periodicity of feeding. Mice fed with ultradian feeding that lost <10% body mass (i.e. isocaloric) displayed 1.5-h phase-advance of body temperature rhythm, but remained mostly nocturnal, together with up-regulated vasopressin and down-regulated PER1 and PER2 levels in the SCN. Hepatic expression of clock genes (Per2, Rev-erbα, and Clock) and Fgf21 was, respectively, phase-advanced and up-regulated by ultradian feeding. Mice fed with ultradian feeding that lost >10% body mass (i.e. hypocaloric) became more diurnal, hypothermic in late night, and displayed larger (3.5 h) advance of body temperature rhythm, more reduced PER1 expression in the SCN, and further modified gene expression in the liver (e.g. larger phase-advance of Per2 and up-regulated levels of Pgc-1α). While glucose rhythmicity was lost under ultradian feeding, the phase of daily rhythms in liver glycogen and plasma corticosterone (albeit increased in amplitude) remained unchanged. In conclusion, the additional impact of hypocaloric conditions on the SCN are mainly due to the metabolic and not the timing effects of restricted daytime feeding.

KEYWORDS:

• Circadian rhythm
• feeding
• 6-meal schedule
• clock gene
• suprachiasmatic nucleus

Acknowledgments

We thank Sylviane Gourmelen and Dr. Dominique Sage-Ciocca for their expert assistance with animal care and actimetry, respectively. We are also indebted to Pr. Paul Pévet for continuous support.

Declaration of interest

The authors report no conflict of interest. This work was supported by a doctoral fellowship from “Neurotime” Erasmus Mundus program (S.S.), and grants from Centre National de la Recherche Scientifique and University of Strasbourg (P.V. and E.C.) and University of Amsterdam (A.K.).