Reduced NRF2/Mfn2 activity promotes endoplasmic reticulum stress and senescence in adipose-derived mesenchymal stem cells in hypertrophic obese mice.

BACKGROUND: Hypertrophy obesity is closely associated with obesity-related metabolic diseases. The senescence of adipose-derived mesenchymal stem cells (ASCs) is believed to play a significant role in the development of hypertrophy obesity. AIM: To investigate the relationship between ASC senescence, endoplasmic reticulum (ER) stress, and nuclear factor erythroid-derived 2 (NRF2) activity in a mouse model of hypertrophy obesity. Additionally, we explored the mechanism through which NRF2 affects ASC senescence via mitofusin-2 (MFN2). METHODS: We observed the senescent phenotype and ER stress (ERS) in ASCs from hypertrophic obese mouse models, and determined NRF2 activity. Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) was used to analyze the transcriptional activity of NRF2 on Mfn2. Additionally, co-immunoprecipitation experiments were conducted to investigate the interaction between MFN2 and binding immunoglobulin protein. The impact of NRF2 and MFN2 on the therapeutic effect of ASC transplantation against insulin resistance was explored through ASC transplantation. RESULTS: The study found significant increases in senescence and ERS, accompanied by decreased NRF2 activity in ASCs from hypertrophic obese mouse models. Simultaneously, chromatin immunoprecipitation-qPCR analysis revealed a reduction in NRF2 transcriptional activity on Mfn2. The downregulation of NRF2 activity and Mfn2 expression promoted senescence and ERS in ASCs, subsequently impacting the anti-insulin resistance effect of ASC transplantation. Furthermore, there exists a direct or indirect binding between MFN2 and binding immunoglobulin protein. CONCLUSION: The research outcomes suggest that NRF2 may regulate ERS and senescence in subcutaneous ASCs of hypertrophic obese mice by modulating Mfn2. These discoveries offer new insights into understanding metabolic diseases associated with hypertrophic obesity and potentially provide a foundation for intervention strategies.