A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity

• Published in: Metabolism, clinical and experimental Vol. 172; p. 156358
• Main Authors: Mund, Christine, Sinha, Anupam, Aderhold, Anika, Mateska, Ivona, Hagag, Eman, Traikov, Sofia, Gercken, Bettina, Soto, Andres, Pollock, Jonathan, Arndt, Lilli, Wölk, Michele, Werner, Natalie, Fodelianaki, Georgia, Subramanian, Pallavi, Chung, Kyoung-Jin, Grossklaus, Sylvia, Langner, Mathias, Elgendy, Mohamed, Grinenko, Tatyana, Wielockx, Ben, Dahl, Andreas, Gericke, Martin, Blüher, Matthias, Coskun, Ünal, Voehringer, David, Fedorova, Maria, Peitzsch, Mirko, Murray, Peter J., Chavakis, Triantafyllos, Alexaki, Vasileia Ismini
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2025
• Subjects: Adipocyte progenitors; Adipocytes - metabolism; Adipogenesis; Adipose tissue; Adipose Tissue - metabolism; Animals; AZIN2; Homeostasis - physiology; Humans; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Obesity - metabolism; Polyamine metabolism; Polyamines - metabolism; Adipocyte progenitors; Obesity; AZIN2; Adipose tissue; Polyamine metabolism
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2025.156358

Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology. We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured. Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2−/− APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers. Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health. AZIN2 is highly expressed in APs. It promotes polyamine acetylation thereby regulating acetyl-CoA levels. AZIN2 deficient APs present strongly increased acetyl-CoA levels and more acH3K27 marks in genes involved in lipid metabolism and senescence. Mice with global or AP-specific AZIN2 deficiency on a high-fat diet exhibit reduced AP numbers and develop exacerbated obesity, inflammation and insulin resistance. [Display omitted] •Expression of polyamine metabolism components in adipose tissue declines with obesity.•AZIN2 promotes polyamine acetylation and regulates acetyl-CoA amounts in adipocyte progenitors.•AZIN2 inhibits de novo adipogenesis via regulation of histone acetylation.•AZIN2 deficiency leads to adipocyte progenitor depletion, obesity, inflammation and insulin resistance.