Abstract

Endogenous circadian clocks have evolved to anticipate 24-hour rhythms in environmental demands. Recent studies suggest that circadian rhythm disruption is a major risk factor for the development of metabolic disorders in humans. Conversely, alterations in energy state can disrupt circadian rhythms of behavior and physiology, creating a vicious circle of metabolic dysfunction. How peripheral energy state affects diurnal food intake, however, is still poorly understood. We here show that the adipokine adiponectin (ADIPOQ) regulates diurnal feeding rhythms through clocks in energy regulatory centers of the mediobasal hypothalamus (MBH). Adipoq-deficient mice show increased rest phase food intake associated with disrupted transcript rhythms of clock and appetite-regulating genes in the MBH. ADIPOQ regulates MBH clocks via AdipoR1-mediated upregulation of the core clock gene Bmal1. BMAL1, in turn, controls expression of orexigenic neuropeptide expression in the MBH. Together, these data reveal a systemic metabolic circuit to regulate central circadian clocks and energy intake.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 to 8.

Article and author information

Author details

  1. Anthony H Tsang

    Institute of Neurobiology, University of Lübeck, Lübeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Christiane E Koch

    Institute of Neurobiology, University of Lübeck, Lübeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Jana-Thabea Kiehn

    Institute of Neurobiology, University of Lübeck, Lübeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Cosima X Schmidt

    Institute of Neurobiology, University of Lübeck, Lübeck, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. 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 (GRK-1957)

  • Henrik Oster

Deutsche Forschungsgemeinschaft (OS353-7/1)

  • Henrik Oster

Volkswagen Foundation (Lichtenberg Professorship)

  • Henrik Oster

Deutsche Forschungsgemeinschaft (OS353-10/1)

  • Henrik Oster

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

Ethics

Animal experimentation: All animal experiments were done after ethical assessment by the institutional animal welfare committee and licensed by the Office of Consumer Protection and Food Safety of the State of Lower Saxony (33.12.42502-04-12/0893, 33.14-42502-04-11/0604 and 33.9-42502-04-12/0748) or the Ministry of Agriculture of the State of Schleswig-Holstein (V 242-7224.122-4 (132-10/13)) in accordance with the German Law of Animal Welfare (TierSchG).

Copyright

© 2020, Tsang 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.

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. Anthony H Tsang
  2. Christiane E Koch
  3. Jana-Thabea Kiehn
  4. Cosima X Schmidt
  5. Henrik Oster
(2020)
An adipokine feedback regulating diurnal food intake rhythms in mice
eLife 9:e55388.
https://doi.org/10.7554/eLife.55388

Share this article

https://doi.org/10.7554/eLife.55388

Further reading

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Eric V Strobl, Eric Gamazon
    Research Article

    Root causal gene expression levels – or root causal genes for short – correspond to the initial changes to gene expression that generate patient symptoms as a downstream effect. Identifying root causal genes is critical towards developing treatments that modify disease near its onset, but no existing algorithms attempt to identify root causal genes from data. RNA-sequencing (RNA-seq) data introduces challenges such as measurement error, high dimensionality and non-linearity that compromise accurate estimation of root causal effects even with state-of-the-art approaches. We therefore instead leverage Perturb-seq, or high-throughput perturbations with single-cell RNA-seq readout, to learn the causal order between the genes. We then transfer the causal order to bulk RNA-seq and identify root causal genes specific to a given patient for the first time using a novel statistic. Experiments demonstrate large improvements in performance. Applications to macular degeneration and multiple sclerosis also reveal root causal genes that lie on known pathogenic pathways, delineate patient subgroups and implicate a newly defined omnigenic root causal model.