Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation

  1. Leonardo VM de Assis  Is a corresponding author
  2. Lisbeth Harder
  3. José Thalles Lacerda
  4. Rex Parsons
  5. Meike Kaehler
  6. Ingolf Cascorbi
  7. Inga Nagel
  8. Oliver Rawashdeh
  9. Jens Mittag
  10. Henrik Oster  Is a corresponding author
  1. University of Lübeck, Germany
  2. Karolinska Institute, Sweden
  3. University of Sao Paulo, Brazil
  4. Queensland University of Technology, Australia
  5. University Hospital Schleswig-Holstein, Germany
  6. University of Queensland, Australia

Abstract

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 - 15% of the liver transcriptome as rhythmic in control and T3 groups, but only 4% of the liver transcriptome (1,033 genes) were rhythmic across both conditions - amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

Data availability

All experimental data was deposited in the Figshare depository (https://doi.org/10.6084/m9.figshare.20376444.v1). Microarray data was deposited in the Gene Expression Omnibus (GEO) database under access code GSE199998 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE199998)

The following data sets were generated

Article and author information

Author details

  1. Leonardo VM de Assis

    Institute of Neurobiology, University of Lübeck, Lübeck, Germany
    For correspondence
    leonardo.deassis@uni-luebeck.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5209-0835
  2. Lisbeth Harder

    Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. José Thalles Lacerda

    Department of Physiology, University of Sao Paulo, Sao Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  4. Rex Parsons

    Faculty of Health, Queensland University of Technology, Kelvin Grove, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Meike Kaehler

    Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Ingolf Cascorbi

    Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Inga Nagel

    Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Oliver Rawashdeh

    Faculty of Medicine, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Jens Mittag

    Institute for Endocrinology and Diabetes - Molecular Endocrinology, University of Lübeck, Lübeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Henrik Oster

    Institute of Neurobiology, University of Lübeck, Lübeck, Germany
    For correspondence
    henrik.oster@uni-luebeck.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1414-7068

Funding

Deutsche Forschungsgemeinschaft (353-10/1; GRK-1957; CRC-296 LocoTact"")

  • Henrik Oster

Deutsche Forschungsgemeinschaft (CRC-296 LocoTact" (TP14).")

  • Jens Mittag

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Matthew A Quinn, Wake Forest School of Medicine, United States

Publication history

  1. Received: April 11, 2022
  2. Accepted: July 25, 2022
  3. Accepted Manuscript published: July 27, 2022 (version 1)

Copyright

© 2022, de Assis et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Leonardo VM de Assis
  2. Lisbeth Harder
  3. José Thalles Lacerda
  4. Rex Parsons
  5. Meike Kaehler
  6. Ingolf Cascorbi
  7. Inga Nagel
  8. Oliver Rawashdeh
  9. Jens Mittag
  10. Henrik Oster
(2022)
Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation
eLife 11:e79405.
https://doi.org/10.7554/eLife.79405

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