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

Susanne Keipert (), Dominik Lutter, Bjoern O. Schroeder, Daniel Brandt, Marcus Ståhlman, Thomas Schwarzmayr, Elisabeth Graf, Helmut Fuchs, Martin Hrabe Angelis, Matthias H. Tschöp, Jan Rozman and Martin Jastroch ()
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Susanne Keipert: Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Dominik Lutter: Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Bjoern O. Schroeder: Institute of Medicine, University of Gothenburg
Daniel Brandt: Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Marcus Ståhlman: Institute of Medicine, University of Gothenburg
Thomas Schwarzmayr: German Research Center for Environmental Health (GmbH)
Elisabeth Graf: German Research Center for Environmental Health (GmbH)
Helmut Fuchs: Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Martin Hrabe Angelis: German Center for Diabetes Research (DZD)
Matthias H. Tschöp: Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Jan Rozman: German Center for Diabetes Research (DZD)
Martin Jastroch: Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-14069-2

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