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

Josef Oeckl, Petra Janovska, Katerina Adamcova, Kristina Bardova, Sarah Brunner, Sebastian Dieckmann, Josef Ecker, Tobias Fromme, Jiri Funda, Thomas Gantert, Piero Giansanti, Maria Soledad Hidrobo, Ondrej Kuda, Bernhard Kuster, Yongguo Li, Radek Pohl, Sabine Schmitt, Sabine Schweizer, Hans Zischka, Petr ZouharJan Kopecky, Martin Klingenspor

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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.

Original languageEnglish
Article number101499
JournalMolecular Metabolism
Volume61
DOIs
StatePublished - Jul 2022

Keywords

  • Brown adipose tissue
  • Fatty acids
  • Futile substrate cycle
  • Lipolysis
  • Re-esterification
  • UCP1-independent thermogenesis

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