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

Klara Piletic, Amir H. Kayvanjoo, Felix Clemens Richter, Mariana Borsa, Ana V. Lechuga-Vieco, Oliver Popp, Sacha Grenet, Jacky Ka Long Ko, Lin Luo, Kristina Zec, Maria Kyriazi, Harriet K. Haysom, Lada Koneva, Stephen Sansom, Philipp Mertins, Fiona Powrie, Ghada Alsaleh and Anna Katharina Simon ()
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Klara Piletic: University of Oxford
Amir H. Kayvanjoo: Max-Delbrück Center for Molecular Medicine in the Helmholtz Association
Felix Clemens Richter: University of Oxford
Mariana Borsa: University of Oxford
Ana V. Lechuga-Vieco: University of Oxford
Oliver Popp: Max-Delbrück Center for Molecular Medicine in the Helmholtz Association
Sacha Grenet: University of Oxford
Jacky Ka Long Ko: University of Oxford
Lin Luo: University of Oxford
Kristina Zec: University of Oxford
Maria Kyriazi: University of Oxford
Harriet K. Haysom: University of Oxford
Lada Koneva: University of Oxford
Stephen Sansom: University of Oxford
Philipp Mertins: Max-Delbrück Center for Molecular Medicine in the Helmholtz Association
Fiona Powrie: University of Oxford
Ghada Alsaleh: University of Oxford
Anna Katharina Simon: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64266-5

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