Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice

Abstract

Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3 signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT.

Data availability

The raw sequencing data and aligned read counts generated as part of this study has been deposited to the NCBI Sequence Read Archive. Accession number: GSE201136; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE201136

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Yanis Zekri

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    For correspondence
    yanis.zekri@ens-lyon.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4925-4610
  2. Romain Guyot

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Inés Garteizgogeascoa Suñer

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Laurence Canaple

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Amandine Gautier Stein

    Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Justine Vily Petit

    Inserm, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Denise Aubert

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Sabine Richard

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Frederic Flamant

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3360-2345
  10. Karine Gauthier

    Institut de Génomique Fonctionnelle de Lyon, École Normale Supérieure de Lyon, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.

Funding

European Union's Horizon 2020 (825753)

  • Frederic Flamant

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 experiments were carried out in accordance with the European Community Council Directive of September 22, 2010 (2010/63/EU) regarding the protection of animals used for experimental and other scientific purposes. The research project was approved by a local animal care and use committee (C2EA015) and authorized by the French Ministry of Research.

Copyright

© 2022, Zekri 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

  • 1,554
    views
  • 261
    downloads
  • 13
    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. Yanis Zekri
  2. Romain Guyot
  3. Inés Garteizgogeascoa Suñer
  4. Laurence Canaple
  5. Amandine Gautier Stein
  6. Justine Vily Petit
  7. Denise Aubert
  8. Sabine Richard
  9. Frederic Flamant
  10. Karine Gauthier
(2022)
Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice
eLife 11:e81996.
https://doi.org/10.7554/eLife.81996

Share this article

https://doi.org/10.7554/eLife.81996

Further reading

    1. Cancer Biology
    2. Genetics and Genomics
    Nicole S Arellano, Shannon E Elf
    Insight

    A new approach helps examine the proportion of cancerous and healthy stem cells in patients with chronic myeloid leukemia and how this influences treatment outcomes.

    1. Cancer Biology
    2. Genetics and Genomics
    Rebecca Warfvinge, Linda Geironson Ulfsson ... Göran Karlsson
    Research Article

    The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1IS (%) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis. The patients with treatment failure after 12 months of therapy had a markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multiomic feature landscape enabled visualization of the primitive fraction as a mixture of molecularly distinct BCR::ABL1+ LSCs and BCR::ABL1-hematopoietic stem cells (HSCs) in variable ratio across patients, and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers. We for the first time show that BCR::ABL1+ LSCs and BCR::ABL1- HSCs can be distinctly separated as CD26+CD35- and CD26-CD35+, respectively. In addition, we found the ratio of LSC/HSC to be higher in patients with prospective treatment failure compared to optimal responders, at diagnosis as well as following 3 months of TKI therapy. Collectively, this data builds a framework for understanding therapy response and adapting treatment by devising strategies to extinguish or suppress TKI-insensitive LSCs.