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

## TL;DR

The study shows that autophagy in fat cells protects against obesity-induced fibrosis by controlling purine release, which signals immune cells to cause tissue scarring.

## Contribution

The study reveals a new role for autophagy in regulating purine metabolism to prevent fibrosis in obese adipose tissue.

## Key findings

- Loss of autophagy in fat cells increases fibrosis in visceral white adipose tissue.
- Autophagy limits the release of purines like xanthine and hypoxanthine, which drive macrophage polarization and fibrosis.
- Purine signaling serves as a checkpoint for fibrosis and could be a therapeutic target in related diseases.

## 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.

The study shows that autophagy in fat cells protects against obesity-induced fibrosis. Autophagy limits the release of purines, a metabolic product, that signals to immune cells to initiate the fibrosis. Purines might be a potential target for reducing tissue fibrosis.