Rev-erbα in the brain is essential for circadian food entrainment

Abstract

Foraging is costly in terms of time and energy. An endogenous food-entrainable system allows anticipation of predictable changes of food resources in nature. Yet the molecular mechanism that controls food anticipation in mammals remains elusive. Here we report that deletion of the clock component Rev-erbα impairs food entrainment in mice. Rev-erbα global knockout (GKO) mice subjected to restricted feeding showed reduced elevations of locomotor activity and body temperature prior to mealtime, regardless of the lighting conditions. The failure to properly anticipate food arrival was accompanied by a lack of phase-adjustment to mealtime of the clock protein PERIOD2 in the cerebellum, and by diminished expression of phosphorylated ERK 1/2 (p-ERK) during mealtime in the mediobasal hypothalamus and cerebellum. Furthermore, brain-specific knockout (BKO) mice for Rev-erbα display a defective suprachiasmatic clock, as evidenced by blunted daily activity under a light-dark cycle, altered free-running rhythm in constant darkness and impaired clock gene expression. Notably, brain deletion of Rev-erbα totally prevented food-anticipatory behaviour and thermogenesis. In response to restricted feeding, brain deletion of Rev-erbα impaired changes in clock gene expression in the hippocampus and cerebellum, but not in the liver. Our findings indicate that Rev-erbα is required for neural network-based prediction of food availability.

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

“…The conditional Rev‐erbα knockout (KO) mice were generated at the Mouse Clinical Institute (Strasbourg, France) in the framework of the European EUMODIC consortium . Details for the genesis of this mouse line are provided elsewhere . To generate brain‐specific KO mice, conditional Rev‐erbα KO individuals were crossed with Nestin Cre transgenic mice (line #003771; Jackson Laboratories, Bar Harbor, ME, USA).…”

“…To generate brain‐specific KO mice, conditional Rev‐erbα KO individuals were crossed with Nestin Cre transgenic mice (line #003771; Jackson Laboratories, Bar Harbor, ME, USA). To improve the efficiency of brain deletion of Rev‐erbα , we generated Rev‐erbα fl/gko ;Nes‐Cre mice, hereafter designated as BKO mice, which carry one floxed allele ( fl ) and one global deleted ( gko ) allele, so that one Rev‐erbα allele is deleted in every cell and, in addition, nervous cells do not express Rev‐erbα because of Nestin‐Cre inactivation of the other Rev‐erbα allele . Controls of BKO mice were Rev‐erbα fl/+ ;Nestin Cre littermates (noted CTRL below), which carry one floxed allele ( fl ) and Cre recombinase transgene under the control of the Nestin promoter, thus impairing the expression of only one Rev‐erbα allele in nervous cells.…”

“…Daily changes in food availability elicit rhythmic behavioural, physiological and hormonal changes in anticipation of food access . Recent data indicate that brain expression of Rev‐erbα largely contributes to the cerebral processes predicting food access because a brain deletion of Rev‐erbα prevents these behavioural and thermogenic responses, whereas a global deletion of Rev‐erbα only reduces food‐anticipatory behaviour and thermogenesis . The daily rhythm of food intake and anticipation of food access may share neuronal substrates and functions, raising the possibility that brain REV‐ERBα also participates in the temporal organisation of the daily feeding pattern.…”

Rev-erbα heterozygosity produces a dose-dependent phenotypic advantage in mice

“…It is known that full loss of Rev-erbα expression does not promote changes in wheel running activity in mice that are exposed to normal light/dark cycles [22,23]. However, Nr1d1 -/mice subjected to constant darkness display a shift in circadian activity, demonstrating that REV-ERB is an important regulator of circadian behavior [22].…”

“…It is known that full loss of Rev-erbα expression does not promote changes in wheel running activity in mice that are exposed to normal light/dark cycles [22,23]. However, Nr1d1 -/mice subjected to constant darkness display a shift in circadian activity, demonstrating that REV-ERB is an important regulator of circadian behavior [22]. Nr1d1 +/mice had normal circadian behavior when compared to wild-type mice in either normal light/dark cycles or in constant darkness, suggesting that the regulation of circadian function is preserved in the Nr1d1 +/mice (Supplemental Fig 1A-B).…”