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Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

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.

SUBMITTER: Niemann B

PROVIDER: S-EPMC9452294 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

Niemann Birte B Haufs-Brusberg Saskia S Puetz Laura L Feickert Martin M Jaeckstein Michelle Y MY Hoffmann Anne A Zurkovic Jelena J Heine Markus M Trautmann Eva-Maria EM Müller Christa E CE Tönjes Anke A Schlein Christian C Jafari Azin A Eltzschig Holger K HK Gnad Thorsten T Blüher Matthias M Krahmer Natalie N Kovacs Peter P Heeren Joerg J Pfeifer Alexander A

Nature 20220705 7926

Brown adipose tissue (BAT) dissipates energy<sup>1,2</sup> and promotes cardiometabolic health<sup>3</sup>. 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 adipo ...[more]

PMID: 35790189

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Project description:Rationale: Brown and beige adipocytes are specialized fat cells that dissipate energy in the form of heat, and hold therapeutic potential for obesity and metabolic diseases. Although in the classical viewpoint brown and beige adipocytes dissipate energy solely via uncoupling protein 1 (UCP1), emerging evidence suggests the importance of non-canonical UCP1-independent energy expenditure in regulating energy expenditure, especially in human beige adipocytes. Leucine zipper-, EF-hand-containing transmembrane protein 1 domain containing 1 (LETMD1) was recently identified as a key protein in maintaining UCP1 expression and the thermogenic activity of brown adipocytes in animal models. But the exact function of LETMD1 and its mechanism of action in human beige adipocytes are unclear. Methods: We tested the function of LETMD1 in human induced pluripotent stem cell (hiPSC)-derived beige adipocytes in vitro in both wildtype (WT) and UCP1 knockout (KO) background. Furthermore, human beige adipocytes harboring a doxycycline-inducible LETMD1 expression cassette were transplanted to NOD/SCID mice and the function of LETMD1 in human beige adipocytes was evaluated in the in vivo setting. RNA-Seq was conducted in normal and LETMD1-overexpressing human beige adipocytes to examine the genes and pathways regulated by LETMD1. Using a knock-in human iPSC line, a preclinical small molecule compound library was screened for compounds increasing LETMD1 expression in human beige adipocytes. The effects of the compound in inducing LETMD1 and UCP1-independent energy expenditure in beige adipocytes were examined in vitro and in animal models. Results: LETMD1 plays an essential role in engaging energy dissipation, in a manner independent of UCP1, in human beige adipocytes. Transplantation of LETMD1-overexpressing human beige adipocytes improved whole-body metabolism of the recipient mice independent of UCP1. Mechanistically LETMD1 enhances the transcription of PPARGC1A, a key regulator of mitochondrial biogenesis. The expression of genes related to UCP1-independent energy expenditure, including creatine futile cycle, was also stimulated upon LETMD1 overexpression. Using LETMD1 reporter human beige adipocytes, SP-8356 was identified as a compound significantly increasing LETMD1 expression. Oral administration of SP-8356 induced genes related to UCP1-independent energy expenditure in beige adipocytes, and counteracted body weight gain and metabolic disorders in mice. Conclusion: Increased LETMD1 action, either genetically or pharmacologically, enhances the non-canonical UCP1-independent energy expenditure in beige adipocytes.

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Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

Publications

Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

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