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Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. German Research Center for Environmental Health (GmbH), Germany; German Center for Diabetes Research (DZD), Germany.ORCID iD: 0000-0002-6618-7379
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Number of Authors: 122020 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 624Article in journal (Refereed) Published
Abstract [en]

Brown adipose thermogenesis increases energy expenditure and relies on uncoupling protein 1 (UCP1), however, UCP1 knock-out mice show resistance to diet-induced obesity at room temperature. Here, the authors show that this resistance relies on FGF21-signaling, inducing the browning of white adipose tissue. 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.

Place, publisher, year, edition, pages
2020. Vol. 11, no 1, article id 624
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Microbiology in the medical area Biological Sciences
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URN: urn:nbn:se:su:diva-179581DOI: 10.1038/s41467-019-14069-2ISI: 000513245600012PubMedID: 32005798OAI: oai:DiVA.org:su-179581DiVA, id: diva2:1416705
Available from: 2020-03-25 Created: 2020-03-25 Last updated: 2020-03-25Bibliographically approved

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Keipert, SusanneLutter, Dominikde Angelis, Martin HrabeJastroch, Martin
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