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Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine

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Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. / Niemann, Birte; Haufs-Brusberg, Saskia; Puetz, Laura; feickert, martin; Jaeckstein, Michelle Y; Hoffmann, Anne; Zurkovic, J; Heine, Markus; Trautmann, Eva-Maria; Müller, CE; Tönies, Anke; Schlein, Christian; Jafari, Azin; Eltzsching, Holger K; Gnad, Thorsten; Blüher, Matthias; Krahmer, Natalie; Kovacs, Peter; Heeren, Jörg; Pfeifer, Alexander.

in: NATURE, Jahrgang 609, Nr. 7926, 08.09.2022, S. 361–368.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Niemann, B, Haufs-Brusberg, S, Puetz, L, feickert, M, Jaeckstein, MY, Hoffmann, A, Zurkovic, J, Heine, M, Trautmann, E-M, Müller, CE, Tönies, A, Schlein, C, Jafari, A, Eltzsching, HK, Gnad, T, Blüher, M, Krahmer, N, Kovacs, P, Heeren, J & Pfeifer, A 2022, 'Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine', NATURE, Jg. 609, Nr. 7926, S. 361–368. https://doi.org/10.1038/s41586-022-05041-0

APA

Niemann, B., Haufs-Brusberg, S., Puetz, L., feickert, M., Jaeckstein, M. Y., Hoffmann, A., Zurkovic, J., Heine, M., Trautmann, E-M., Müller, CE., Tönies, A., Schlein, C., Jafari, A., Eltzsching, H. K., Gnad, T., Blüher, M., Krahmer, N., Kovacs, P., Heeren, J., & Pfeifer, A. (2022). Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. NATURE, 609(7926), 361–368. https://doi.org/10.1038/s41586-022-05041-0

Vancouver

Niemann B, Haufs-Brusberg S, Puetz L, feickert M, Jaeckstein MY, Hoffmann A et al. Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine. NATURE. 2022 Sep 8;609(7926):361–368. https://doi.org/10.1038/s41586-022-05041-0

Bibtex

@article{da2587bca2ea40a0b59bbfad3604dd8c,
title = "Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine",
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 {\textquoteleft}browning{\textquoteright} 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 {\textquoteleft}replace me{\textquoteright} signalling function that regulates thermogenic fat and counteracts obesity.",
author = "Birte Niemann and Saskia Haufs-Brusberg and Laura Puetz and martin feickert and Jaeckstein, {Michelle Y} and Anne Hoffmann and J Zurkovic and Markus Heine and Eva-Maria Trautmann and CE M{\"u}ller and Anke T{\"o}nies and Christian Schlein and Azin Jafari and Eltzsching, {Holger K} and Thorsten Gnad and Matthias Bl{\"u}her and Natalie Krahmer and Peter Kovacs and J{\"o}rg Heeren and Alexander Pfeifer",
year = "2022",
month = sep,
day = "8",
doi = "10.1038/s41586-022-05041-0",
language = "English",
volume = "609",
pages = "361–368",
journal = "NATURE",
issn = "0028-0836",
publisher = "NATURE PUBLISHING GROUP",
number = "7926",

}

RIS

TY - JOUR

T1 - Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine

AU - Niemann, Birte

AU - Haufs-Brusberg, Saskia

AU - Puetz, Laura

AU - feickert, martin

AU - Jaeckstein, Michelle Y

AU - Hoffmann, Anne

AU - Zurkovic, J

AU - Heine, Markus

AU - Trautmann, Eva-Maria

AU - Müller, CE

AU - Tönies, Anke

AU - Schlein, Christian

AU - Jafari, Azin

AU - Eltzsching, Holger K

AU - Gnad, Thorsten

AU - Blüher, Matthias

AU - Krahmer, Natalie

AU - Kovacs, Peter

AU - Heeren, Jörg

AU - Pfeifer, Alexander

PY - 2022/9/8

Y1 - 2022/9/8

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-022-05041-0

DO - 10.1038/s41586-022-05041-0

M3 - SCORING: Journal article

C2 - 35790189

VL - 609

SP - 361

EP - 368

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7926

ER -