Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling

A hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Using a mouse model, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy restrains purine nucleoside metabolism in obese adipocytes. This ultimately leads to a reduced release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings in mice reveal a role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases.

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Publication Details

Journal
Nature Communications
Published
2025-10-17
DOI
https://doi.org/10.1038/s41467-025-64266-5
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
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article

Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling

Felix Clemens Richter, Amir Hossein Kayvanjoo, Kristina Zec, Klara Piletič et al.
Nature Communications
Autophagy in Disease and Therapy
article

Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling

Felix Clemens Richter, Amir Hossein Kayvanjoo, Kristina Zec, Klara Piletič, Fiona Powrie, Philipp Mertins, Anna Katharina Simon, Ana Victoria Lechuga‐Vieco, Harriet K. Haysom, Ghada Alsaleh, Lada A. Koneva, Oliver Popp, Maria Kyriazi, Stephen N. Sansom, Mariana Borsa, Lin Luo, Sacha Grenet, Jacky Ka Long Ko
article en

Abstract

A hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Using a mouse model, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy restrains purine nucleoside metabolism in obese adipocytes. This ultimately leads to a reduced release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings in mice reveal a role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases.

Nature CommunicationsVol. 16(1)
Université Claude Bernard Lyon 1 (FR), École Normale Supérieure de Lyon (FR), Helmholtz Association of German Research Centres (DE), Memorial Sloan Kettering Cancer Center (US), Max Delbrück Center (DE), Nuffield Orthopaedic Centre (GB), University of Oxford (GB), NIHR Oxford Musculoskeletal Biomedical Research Centre (GB), Kennedy Center (DK)
Openalex Percentile: Top 60%
Autophagy in Disease and Therapy
DOIOpen Access PDFOpenAlex
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