OBJECTIVE: Classical ATP-independent non-shivering thermogenesis enabled by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is activated, but not essential for survival, in the cold. It has long been suspected that futile ATP-consuming substrate cycles also contribute to thermogenesis and can partially compensate for the genetic ablation of UCP1 in mouse models. Futile ATP-dependent thermogenesis could thereby enable survival in the cold even when brown fat is less abundant or missing. METHODS: In this study, we explore different potential sources of UCP1-independent thermogenesis and identify a futile ATP-consuming triglyceride/fatty acid cycle as the main contributor to cellular heat production in brown adipocytes lacking UCP1. We uncover the mechanism on a molecular level and pinpoint the key enzymes involved using pharmacological and genetic interference. RESULTS: ATGL is the most important lipase in terms of releasing fatty acids from lipid droplets, while DGAT1 accounts for the majority of fatty acid re-esterification in UCP1-ablated brown adipocytes. Furthermore, we demonstrate that chronic cold exposure causes a pronounced remodeling of adipose tissues and leads to the recruitment of lipid cycling capacity specifically in BAT of UCP1-knockout mice, possibly fueled by fatty acids from white fat. Quantification of triglyceride/fatty acid cycling clearly shows that UCP1-ablated animals significantly increase turnover rates at room temperature and below. CONCLUSION: Our results suggest an important role for futile lipid cycling in adaptive thermogenesis and total energy expenditure.

Chair for Molecular Nutritional Medicine TUM School of Life Sciences Technical University of Munich Freising Germany; EKFZ Else Kröner Fresenius Center for Nutritional Medicine Technical University of Munich Freising Germany; ZIEL Institute for Food and Health Technical University of Munich Freising Germany

Chair of Proteomics and Bioanalytics TUM School of Life Sciences Technical University of Munich Freising Germany; Bavarian Center for Biomolecular Mass Spectrometry Technical University of Munich Freising Germany

Institute of Toxicology and Environmental Hygiene School of Medicine Technical University of Munich Munich Germany

Institute of Toxicology and Environmental Hygiene School of Medicine Technical University of Munich Munich Germany; Institute of Molecular Toxicology and Pharmacology Helmholtz Center Munich Munich Germany

Laboratory of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences Czech Republic

Laboratory of Metabolism of Bioactive Lipids Institute of Physiology of the Czech Academy of Sciences Czech Republic

NMR spectroscopy Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Czech Republic

ZIEL Institute for Food and Health Technical University of Munich Freising Germany

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

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