Ablation of miRNA-22 protects against obesity-induced adipocyte senescence and ameliorates metabolic disorders in middle-aged mice

• Published in: Mechanisms of ageing and development Vol. 210; p. 111775
• Main Authors: Lino, Caroline A., de Oliveira-Silva, Tábatha, Lunardon, Guilherme, Balbino-Silva, Camila, Lima, Vanessa M., Huang, Zhan-Peng, Donato Jr, Jose, Takano, Ana Paula C., Barreto-Chaves, Maria Luiza, Wang, Da-Zhi, Diniz, Gabriela P.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01-03-2023
• Subjects: Adipocytes - metabolism; Adipose Tissue, White - metabolism; Animals; Cellular senescence; H2ax; Metabolic Diseases - genetics; Metabolic Diseases - prevention & control; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; MiRNA-22; Obesity; Obesity - genetics; Obesity - metabolism; White adipose tissue; H2ax; Obesity; White adipose tissue; MiRNA-22; Cellular senescence
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2023.111775

High-fat diet (HFD) promotes obesity-related metabolic complications by activating cellular senescence in white adipose tissue (WAT). Growing evidence supports the importance of microRNA-22 (miR-22) in metabolic disorders and cellular senescence. Recently, we showed that miR-22 deletion attenuates obesity-related metabolic abnormalities. However, whether miR-22 mediates HFD-induced cellular senescence of WAT remains unknown. Here, we uncovered that obese mice displayed increased pri-miR-22 levels and cellular senescence in WAT. However, miR-22 ablation protected mice against HFD-induced WAT senescence. In addition, in vitro studies showed that miR-22 deletion prevented preadipocyte senescence in response to Doxorubicin (Doxo). Loss-of-function studies in vitro and in vivo revealed that miR-22 increases H2ax mRNA and γH2ax levels in preadipocytes and WAT without inducing DNA damage. Intriguingly, miR-22 ablation prevented HFD-induced increase in γH2ax levels and DNA damage in WAT. Similarly, miR-22 deletion prevented Doxo-induced increase in γH2ax levels in preadipocytes. Adipose miR-22 levels were enhanced in middle-aged mice fed a HFD than those found in young mice. Furthermore, miR-22 deletion attenuated fat mass gain and glucose imbalance induced by HFD in middle-aged mice. Overall, our findings indicate that miR-22 is a key regulator of obesity-induced WAT senescence and metabolic disorders in middle-aged mice.
•The mechanisms involved in obesity-induced white adipose tissue senescence remain not fully understood.•Deletion of miR-22 prevented high-fat diet-induced white adipose tissue, senescence and DNA damage.•Ablation of miR-22 prevented Doxorubicin-induced preadipocyte senescence in vitro.•Deletion of miR-22 attenuated high-fat diet-induced metabolic disorders in middle-aged mice.•miR-22 is a key regulator of obesity-induced white adipose tissue senescence and metabolic disorders in middle-aged mice.