Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine

Birte Niemann (), Saskia Haufs-Brusberg, Laura Puetz, Martin Feickert, Michelle Y. Jaeckstein, Anne Hoffmann, Jelena Zurkovic, Markus Heine, Eva-Maria Trautmann, Christa E. Müller, Anke Tönjes, Christian Schlein, Azin Jafari, Holger K. Eltzschig, Thorsten Gnad, Matthias Blüher, Natalie Krahmer, Peter Kovacs, Joerg Heeren and Alexander Pfeifer ()
Additional contact information
Birte Niemann: University Hospital, University of Bonn
Saskia Haufs-Brusberg: University Hospital, University of Bonn
Laura Puetz: University Hospital, University of Bonn
Martin Feickert: University Hospital, University of Bonn
Michelle Y. Jaeckstein: University Medical Center Hamburg-Eppendorf
Anne Hoffmann: Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig
Jelena Zurkovic: University Hospital, University of Bonn
Markus Heine: University Medical Center Hamburg-Eppendorf
Eva-Maria Trautmann: Helmholtz Center Munich
Christa E. Müller: University of Bonn
Anke Tönjes: University of Leipzig Medical Center
Christian Schlein: University Medical Center Hamburg-Eppendorf
Azin Jafari: University Hospital, University of Bonn
Holger K. Eltzschig: University of Texas Health Science Center at Houston, McGovern Medical School
Thorsten Gnad: University Hospital, University of Bonn
Matthias Blüher: Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig
Natalie Krahmer: Helmholtz Center Munich
Peter Kovacs: University of Leipzig Medical Center
Joerg Heeren: University Medical Center Hamburg-Eppendorf
Alexander Pfeifer: University Hospital, University of Bonn

Nature, 2022, vol. 609, issue 7926, 361-368

Abstract: Abstract Brown adipose tissue (BAT) dissipates energy1,2 and promotes cardiometabolic health3. Loss of BAT during obesity and ageing is a principal hurdle for BAT-centred obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. This apoptotic secretome enhances expression of the thermogenic programme in healthy adipocytes. This effect is mediated by the purine inosine that stimulates energy expenditure in brown adipocytes by the cyclic adenosine monophosphate–protein kinase A signalling pathway. Treatment of mice with inosine increased BAT-dependent energy expenditure and induced ‘browning’ of white adipose tissue. Mechanistically, the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) regulates inosine levels in BAT: ENT1-deficiency increases extracellular inosine levels and consequently enhances thermogenic adipocyte differentiation. In mice, pharmacological inhibition of ENT1 as well as global and adipose-specific ablation enhanced BAT activity and counteracted diet-induced obesity, respectively. In human brown adipocytes, knockdown or blockade of ENT1 increased extracellular inosine, which enhanced thermogenic capacity. Conversely, high ENT1 levels correlated with lower expression of the thermogenic marker UCP1 in human adipose tissues. Finally, the Ile216Thr loss of function mutation in human ENT1 was associated with significantly lower body mass index and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with a ‘replace me’ signalling function that regulates thermogenic fat and counteracts obesity.

Date: 2022
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05041-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:609:y:2022:i:7926:d:10.1038_s41586-022-05041-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05041-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().