Adipocyte autophagy in the control of obese white adipose tissue dysfunction

Thesis

Diet-induced obesity (DIO) leads to a pathological expansion of white adipose tissue (WAT), hallmarked by low-grade chronic inflammation and fibrosis. Autophagy, an evolutionary highly conserved cellular recycling pathway, positively associates with increased adiposity. However, while its role in supporting adipocyte differentiation and lipid homeostasis is well established, little is known about its role in obese adipocytes and adipose tissue dysfunction.

Here, we demonstrate that autophagy serves as a key regulator of WAT remodelling and distribution in DIO. We uncover that loss of autophagy in mature adipocytes significantly and specifically exacerbates pericellular fibrosis of gonadal WAT (gWAT), allowing for greater deposition of fat in the subcutaneous depot and supporting metabolically healthier obesity (MHO). Importantly, changes in WAT architecture are associated with increased macrophage infiltration which carry tissue-reparative and pro-fibrotic features and likely drive gWAT fibrosis. Mechanistically, we uncover that autophagy is indispensable for obesity-induced adipocyte metabolic rewiring and limits purine nucleoside catabolism. Purine catabolites, including xanthine and hypoxanthine, are secreted from adipocytes to mediate adipocyte-macrophage crosstalk, thereby directing macrophage identity towards a tissue-reparative phenotype and contributing to excessive gWAT fibrosis.

The findings of this thesis reveal a novel role for adipocyte autophagy in the maintenance of the functional integrity and dynamic remodelling of gWAT through the limitation of obesity-associated fibrosis. Furthermore, the data presented here uncovers the role of autophagy in the regulation of adipocyte purine nucleoside metabolism and corresponding extracellular signals, which may hold therapeutic potential in fibrotic diseases.

Authors: Piletič, K

• DOI: 10.5287/ora-ozqa4rmgp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: adipocyte; autophagy; macrophage; purine nucleoside metabolism; fibrosis; white adipose tissue; obesity
• Subjects: Adipose tissues; Obesity--Animal models; Fat cells; Cellular immunity; Molecular immunology