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

• Published in: Nature communications Vol. 11; no. 1; pp. 624 - 12
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 38/91; 631/443; 631/443/319; 64/110; 64/60; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; Animal models; Animals; balance; bile-acids; brown adipose-tissue; Browning; Cardiac and Cardiovascular Systems; cold-exposure; Diet; diet-induced thermogenesis; Endocrinology and Diabetes; Endokrinologi och diabetes; Energy expenditure; Energy Metabolism; fat; fgf21; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Humanities and Social Sciences; Humans; Kardiologi; Lipid metabolism; Lipids; Male; Metabolism; Metabolomics; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Obesity; Obesity - genetics; Obesity - metabolism; Organs; Oxidative metabolism; Proteins; Resistance factors; Room temperature; Science; Science & Technology - Other Topics; Science (multidisciplinary); Signal Transduction; Signaling; Thermogenesis; ucp1; Uncoupling protein 1; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism; Urine; white
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14069-2

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. 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.