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Oeckl, J.* ; Janovska, P.* ; Adamcova, K.* ; Bardova, K.* ; Brunner, S.* ; Dieckmann, S.* ; Ecker, J.* ; Fromme, T.* ; Funda, J.* ; Gantert, T.* ; Giansanti, P.* ; Hidrobo, M.S.* ; Kuda, O.* ; Kuster, B.* ; Li, Y.* ; Pohl, R.* ; Schmitt, S.* ; Schweizer, S.* ; Zischka, H. ; Zouhar, P.* ; Kopecky, J.* ; Klingenspor, M.*

Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat.

Mol. Metab. 61:101499 (2022)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Brown Adipose Tissue ; Fatty Acids ; Futile Substrate Cycle ; Lipolysis ; Re-esterification ; Ucp1-independent Thermogenesis

ISSN (print) / ISBN 2212-8778

e-ISSN 2212-8778

Journal Molecular Metabolism

Quellenangaben Volume: 61, Article Number: 101499

Publisher Elsevier

Publishing Place Amsterdam

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Molecular Toxicology and Pharmacology (TOXI)

Grants Grant Agency of the Czech Republic
ZIEL-Institute for Food Health
Else Krner Fresenius Stiftung
German Research Foundation (DFG)