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

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Lino, Caroline A. ; de Oliveira-Silva, Tabatha ; Lunardon, Guilherme ; Balbino-Silva, Camila ; Lima, Vanessa M. ; Huang, Zhan-Peng ; Donato, Jose ; Takano, Ana Paula C. ; Barreto-Chaves, Maria Luiza ; Wang, Da-Zhi ; Diniz, Gabriela P.

• Tipo de documento: Artigo Científico
• Fonte: MECHANISMS OF AGEING AND DEVELOPMENT; v. 210, p. 14-pg., 2023-01-16.

Resumo

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-offunction studies in vitro and in vivo revealed that miR-22 increases H2ax mRNA and gamma H2ax levels in preadipocytes and WAT without inducing DNA damage. Intriguingly, miR-22 ablation prevented HFD-induced increase in gamma H2ax levels and DNA damage in WAT. Similarly, miR-22 deletion prevented Doxo-induced increase in gamma H2ax 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. (AU)

• Processo FAPESP: 18/10338-2 - Impacto do microRNA-22 na diferenciação de adipócitos marrons e no processo de browning do tecido adiposo branco
• Beneficiário: Gabriela Placoná Diniz
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/13211-3 - Impacto do microRNA-22 e da senescência celular nas disfunções metabólicas induzidas pela obesidade
• Beneficiário: Gabriela Placoná Diniz
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/21491-6 - Impacto do miRNA-22 e da senescência celular nas disfunções metabólicas induzidas pela obesidade
• Beneficiário: Caroline Antunes Lino
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado