Title

Desynchrony between brain and peripheral clocks caused by CK1delta/epsilon disruption in GABA neurons does not lead to adverse metabolic outcomes

UMMS Affiliation

Department of Neurobiology; Weaver Lab

Publication Date

2018-03-06

Document Type

Article

Disciplines

Neuroscience and Neurobiology

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 (Vgat-Cre(+)CK1delta(fl/fl)epsilon(fl/+) ) 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 ( approximately 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.

Keywords

PER2::luciferase, circadian, clock genes, peripheral oscillator, suprachiasmatic nucleus

DOI of Published Version

10.1073/pnas.1712324115

Source

Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2437-E2446. doi: 10.1073/pnas.1712324115. Epub 2018 Feb 20. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

29463694

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