Desynchrony between brain and peripheral clocks caused by CK1δ/ε disruption in GABA neurons does not lead to adverse metabolic outcomes

Abstract

Circadian disruption as a result of shift work is associated with adverse metabolic consequences. Internal desynchrony between the phase of the suprachiasmatic nuclei (SCN) and peripheral clocks is widely believed to be a major factor contributing to these adverse consequences, but this hypothesis has never been tested directly. A GABAergic Cre driver combined with conditional casein kinase mutations ( ) was used to lengthen the endogenous circadian period in GABAergic neurons, including the SCN, but not in peripheral tissues, to create a Discordant mouse model. These mice had a long (27.4 h) behavioral period to which peripheral clocks entrained in vivo albeit with an advanced phase (∼6 h). Thus, in the absence of environmental timing cues, these mice had internal desynchrony between the SCN and peripheral clocks. Surprisingly, internal desynchrony did not result in obesity in this model. Instead, Discordant mice had reduced body mass compared with Cre-negative controls on regular chow and even when challenged with a high-fat diet. Similarly, internal desynchrony failed to induce glucose intolerance or disrupt body temperature and energy expenditure rhythms. Subsequently, a lighting cycle of 2-h light/23.5-h dark was used to create a similar internal desynchrony state in both genotypes. Under these conditions, Discordant mice maintained their lower body mass relative to controls, suggesting that internal desynchrony did not cause the lowered body mass. Overall, our results indicate that internal desynchrony does not necessarily lead to metabolic derangements and suggest that additional mechanisms contribute to the adverse metabolic consequences observed in circadian disruption protocols.

Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes

“…According to this last hypothesis, food mistiming can uncouple peripheral clocks in metabolic tissues from the central clock, causing internal misalignment [41]. However, to date, there is no direct evidence that internal desynchrony per se adversely affects glucose control [42], suggesting that the first two mechanisms may be most important.…”

Circadian rhythms and obesity: Timekeeping governs lipid metabolism

“…22,23 For example, CK1δ/ε is a priming kinase for PER2 phosphorylation and a Discordant mouse model caused by CK1δ/ε disruption in GABAergic neurons shows a long (27.4 hour) behavioral period. 24 Hence, the current view is that circadian rhythms are governed by a very complex system that works in a well-organized way to coordinate endogenous circadian rhythms in gene expression and physiological metabolism. The analysis of the circadian transcriptome in 12 mouse organs demonstrated that more than 40% of all protein coding genes and 1,000 noncoding RNAs oscillate in an organ-specific manner and many of these rhythmic transcripts peaked during transcriptional "rush hours" preceding dawn and dusk.…”

Clocks and meals keep mice from being cool

“…At the molecular level, mammalian circadian clocks consist of transcription-translation feedback loops in which positive limb proteins (BMAL1, CLOCK and NPAS2) drive the expression of negative limb proteins (PERIOD1-3 and CRYPTOCHROME1-2), which subsequently inhibit the activity of the positive limb (Takahashi, 2017). This molecular feedback loop has a period of ∼24 h. The period length is set by the degradation rate of negative limb proteins, with casein kinase 1 delta and epsilon (CK1δ/ε) being important for setting the speed of the clock by controlling the stability of PERIOD proteins (Etchegaray et al, 2009;Meng et al, 2008;van der Vinne et al, 2018). The molecular components of the circadian clockwork are widely expressed, and cell-autonomous circadian clocks are present in nearly all cells of the body.…”