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Chronobiol Int. 2017;34(1):17-36. doi: 10.1080/07420528.2016.1231689. Epub 2016 Sep 26.

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

Author information

  • 1a Regulation of Circadian Clocks team , Institute of Cellular and Integrative Neurosciences, UPR3212, Centre National de la Recherche Scientifique (CNRS), University of Strasbourg , Strasbourg , France.
  • 2b Hypothalamic Integration Mechanisms , Netherlands Institute for Neuroscience (NIN) , Amsterdam , The Netherlands.
  • 3c International Associated Laboratory LIA1061 Understanding the Neural Basis of Diurnality, CNRS , Strasbourg, France and Amsterdam , The Netherlands.
  • 4d Department of Endocrinology and Metabolism , Academic Medical Center (AMC), University of Amsterdam , Amsterdam , The Netherlands.


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.


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

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