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Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unkn...

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Autores principales: Keipert, Susanne, Lutter, Dominik, Schroeder, Bjoern O., Brandt, Daniel, Ståhlman, Marcus, Schwarzmayr, Thomas, Graf, Elisabeth, Fuchs, Helmut, de Angelis, Martin Hrabe, Tschöp, Matthias H., Rozman, Jan, Jastroch, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994690/
https://www.ncbi.nlm.nih.gov/pubmed/32005798
http://dx.doi.org/10.1038/s41467-019-14069-2
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author Keipert, Susanne
Lutter, Dominik
Schroeder, Bjoern O.
Brandt, Daniel
Ståhlman, Marcus
Schwarzmayr, Thomas
Graf, Elisabeth
Fuchs, Helmut
de Angelis, Martin Hrabe
Tschöp, Matthias H.
Rozman, Jan
Jastroch, Martin
author_facet Keipert, Susanne
Lutter, Dominik
Schroeder, Bjoern O.
Brandt, Daniel
Ståhlman, Marcus
Schwarzmayr, Thomas
Graf, Elisabeth
Fuchs, Helmut
de Angelis, Martin Hrabe
Tschöp, Matthias H.
Rozman, Jan
Jastroch, Martin
author_sort Keipert, Susanne
collection PubMed
description Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1.
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spelling pubmed-69946902020-02-03 Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice Keipert, Susanne Lutter, Dominik Schroeder, Bjoern O. Brandt, Daniel Ståhlman, Marcus Schwarzmayr, Thomas Graf, Elisabeth Fuchs, Helmut de Angelis, Martin Hrabe Tschöp, Matthias H. Rozman, Jan Jastroch, Martin Nat Commun Article Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1. Nature Publishing Group UK 2020-01-31 /pmc/articles/PMC6994690/ /pubmed/32005798 http://dx.doi.org/10.1038/s41467-019-14069-2 Text en © The Author(s) 2020, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Keipert, Susanne
Lutter, Dominik
Schroeder, Bjoern O.
Brandt, Daniel
Ståhlman, Marcus
Schwarzmayr, Thomas
Graf, Elisabeth
Fuchs, Helmut
de Angelis, Martin Hrabe
Tschöp, Matthias H.
Rozman, Jan
Jastroch, Martin
Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
title Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
title_full Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
title_fullStr Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
title_full_unstemmed Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
title_short Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
title_sort endogenous fgf21-signaling controls paradoxical obesity resistance of ucp1-deficient mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994690/
https://www.ncbi.nlm.nih.gov/pubmed/32005798
http://dx.doi.org/10.1038/s41467-019-14069-2
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