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
Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Department of Infection Biology, Universitätsklinikum Erlangen and Friedrich-Alexander, University Erlangen-Nürnberg, Erlangen, Germany.
Metabolism. 2025 Nov;172:156358. doi: 10.1016/j.metabol.2025.156358. Epub 2025 Aug 5.
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.
脂肪组织功能是全身代谢稳态不可或缺的一部分。过多的脂肪组织生长与慢性低度炎症及全身代谢紊乱的发生相关。调节脂肪组织生长和稳态的细胞代谢途径尚不清楚。在此，我们研究了多胺代谢在脂肪组织（病理）生理学中的作用。
我们构建了全身及脂肪细胞祖细胞（AP）特异性抗酶抑制剂2（AZIN2）缺陷的小鼠，并进行了饮食诱导肥胖研究。从小鼠的皮下和性腺脂肪组织中分离出AP并进行培养。
包括AZIN2在内的多胺代谢成分在AP中高度表达，且其在脂肪组织中的表达随肥胖而下调。白细胞介素4诱导AP中Azin2的表达。AZIN2促进多胺合成和乙酰化，并调节AP中的总乙酰辅酶A水平。AZIN2缺陷上调了与脂质代谢相关基因的组蛋白乙酰化。与野生型相比，Azin2 AP在体内和体外更有效地向脂肪生成分化，且更易衰老。在饮食诱导肥胖后，小鼠全身及AP特异性AZIN2缺陷导致AP耗竭、脂肪细胞肥大、肥胖、炎症、葡萄糖不耐受和胰岛素抵抗。在人类脂肪组织中，AZIN2表达与祖细胞标志物的表达密切相关。
总之，我们确定AZIN2是一种新型的AP标志物，可调节AP命运并维持脂肪组织健康。
