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.

Chair of Experimental Genetics School of Life Science Weihenstephan Technische Universität München 85354 Freising Germany

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences BIOCEV 252 50 Vestec Czech Republic

Department of Molecular Biosciences The Wenner Gren Institute Stockholm University 106 91 Stockholm Sweden

Division of Metabolic Diseases Department of Medicine Technische Universität Munich Germany

German Center for Diabetes Research 85764 Neuherberg Germany

German Mouse Clinic Institute of Experimental Genetics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Institute for Diabetes and Obesity Helmholtz Diabetes Center Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Institute of Human Genetics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Laboratory for Molecular Infection Medicine Sweden and Department of Molecular Biology Umeå University 901 87 Umeå Sweden

Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Institute of Medicine University of Gothenburg 413 45 Göteborg Sweden

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Nat Commun. 2021 Mar 16;12(1):1804. doi: 10.1038/s41467-021-22119-x. PubMed

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Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity

Highly recruited brown adipose tissue does not in itself protect against obesity

Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle