Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine PMID: 35790189

ADC Targets in Oncology

2026-04-10

Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine

Nature. 2022 Sep;609(7926):361-368. doi: 10.1038/s41586-022-05041-0.

Birte Niemann ^# ¹ , Saskia Haufs-Brusberg ^# ² , Laura Puetz ² , Martin Feickert ² , Michelle Y Jaeckstein ³ , Anne Hoffmann ⁴ , Jelena Zurkovic ² , Markus Heine ³ , Eva-Maria Trautmann ⁵ , Christa E Müller ⁶ ⁷ , Anke Tönjes ⁸ , Christian Schlein ⁹ , Azin Jafari ¹⁰ , Holger K Eltzschig ¹¹ , Thorsten Gnad ² , Matthias Blüher ⁴ ⁸ , Natalie Krahmer ⁵ ¹² , Peter Kovacs ⁸ , Joerg Heeren ³ , Alexander Pfeifer ¹³ ¹⁴

Affiliations

1. Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany. [email protected].
2. Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany.
3. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
4. Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
5. Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany.
6. Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany.
7. PharmaCenter Bonn, University of Bonn, Bonn, Germany.
8. Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
9. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
10. Clinic and Polyclinic for General, Visceral, Thoracic and Vascular Surgery, University Hospital, University of Bonn, Bonn, Germany.
11. Department of Anesthesiology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas, USA.
12. German Center for Diabetes Research (DZD), Neuherberg, Germany.
13. Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany. [email protected].
14. PharmaCenter Bonn, University of Bonn, Bonn, Germany. [email protected].
# Contributed equally.

Abstract

Brown adipose tissue (BAT) dissipates energy^1,2 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.