Oxyntomodulin regulates resetting of the liver circadian clock by food

  1. Dominic Landgraf
  2. Anthony H Tsang
  3. Alexei Leliavski
  4. Christiane E Koch
  5. Johanna L Barclay
  6. Daniel J Drucker
  7. Henrik Oster  Is a corresponding author
  1. University of California, San Diego, United States
  2. Max Planck Institute for Biophysical Chemistry, Germany
  3. University of Lübeck, Germany
  4. University of Toronto, Canada

Abstract

Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light-dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. Here we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues.

Article and author information

Author details

  1. Dominic Landgraf

    Department of Psychiatry, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anthony H Tsang

    Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexei Leliavski

    Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Christiane E Koch

    Chronophysiology Group, Medical Department I, University of Lübeck, Lübeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Johanna L Barclay

    Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel J Drucker

    Department of Medicine, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Henrik Oster

    Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    For correspondence
    henrik.oster@uksh.de
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the German law for animal welfare (TierschGes). All animals were handled according to approved institutional animal care and use committee protocols of the Max Planck Institutes Göttingen and the University of Lübeck. The protocol was approved by the ethical committees of the Niedersächsisches Amt für Verbraucherschutz und Lebensmittelsicherheit (LAVES) and the Ministerium für Energiewende, Landwirtschaft, Umwelt und ländliche Räume (MELUR; license numbers V312-7224.122-4 and 33.12-42502-04-12/0893). Every effort was made to minimize suffering

Copyright

© 2015, Landgraf 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.

Metrics

  • 3,005
    views
  • 775
    downloads
  • 88
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Dominic Landgraf
  2. Anthony H Tsang
  3. Alexei Leliavski
  4. Christiane E Koch
  5. Johanna L Barclay
  6. Daniel J Drucker
  7. Henrik Oster
(2015)
Oxyntomodulin regulates resetting of the liver circadian clock by food
eLife 4:e06253.
https://doi.org/10.7554/eLife.06253

Share this article

https://doi.org/10.7554/eLife.06253

Further reading

    1. Biochemistry and Chemical Biology
    2. Cancer Biology
    Flavie Coquel, Sing-Zong Ho ... Philippe Pasero
    Research Article

    Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies.

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Santi Mestre-Fos, Lucas Ferguson ... Jamie HD Cate
    Research Article

    Stem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA) Seq, we show eIF3 crosslinks predominantly with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling, but not with translational efficiency. The results presented here show that eIF3 engages with 3’-UTR termini of highly translated mRNAs, likely reflecting a general rather than specific regulatory function of eIF3, and supporting a role of mRNA circularization in the mechanisms governing mRNA translation.