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

Feb 22, 2018Proceedings of the National Academy of Sciences of the United States of America

Disrupted timing between brain and body clocks in inhibitory neurons does not cause metabolic problems

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Abstract

Mice with a 27.4-hour behavioral period exhibited internal desynchrony without resulting in obesity.

Circadian disruption from shift work is linked to negative metabolic effects.
Internal desynchrony between the brain's clock and peripheral clocks was created in mice.
Despite this internal desynchrony, these mice showed reduced body mass compared to controls.
Internal desynchrony did not lead to glucose intolerance or disrupt energy expenditure patterns.
Similar conditions in both genotypes confirmed that internal desynchrony did not cause lower body mass.
Additional mechanisms may contribute to the metabolic consequences associated with circadian disruption.

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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 vivoalbeit 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. Vgat-Cre CK1δ ε, + fl/fl fl/+

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

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