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)
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
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Keywords
Brown Adipose Tissue ; Fatty Acids ; Futile Substrate Cycle ; Lipolysis ; Re-esterification ; Ucp1-independent Thermogenesis
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Language
english
Publication Year
2022
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2022
ISSN (print) / ISBN
2212-8778
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2212-8778
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Quellenangaben
Volume: 61,
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Article Number: 101499
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Elsevier
Publishing Place
Amsterdam
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Peer reviewed
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-505200-003
Grants
Grant Agency of the Czech Republic
ZIEL-Institute for Food Health
Else Krner Fresenius Stiftung
German Research Foundation (DFG)
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Erfassungsdatum
2022-08-31