Nucleus‐localized adiponectin is survival gatekeeper through miR‐214‐mediated AIFM2 regulation

: Adiponectin secreted from adipocytes into plasma has anti-aging, anti-obesity and anti-inflammation effects. Here, we detected intracellular adiponectin localized in the nuclei of human and mouse pluripotent stem cells, mouse germ cells and some somatic cells. Nucleus-localized (Nu) adiponectin protein is characterized by an N-terminal truncated monomer form in a native state, compared with intact multimer forms of cytoplasm-localized (Cy) adiponectin protein. Doxycycline-induced over-expression of ADIPONECTIN caused cell death in human and mouse Nu-type pluripotent stem cells. Genome-wide gene expression analysis indicated that apoptosis by ADIPONECTIN over-expression was induced in accompany with upregulation of AIFM2 and MEG3. Upregulation of AIFM2 and MEG3 and down-regulation of miR-214-3p verified by qPCR analyses after ADIPONECTIN over-expression indicated that the MEG3/miR-214/AIFM2 pathway played a role in the apoptotic cell death of pluripotent cells. Adiponectin-induced cell death was rescued by the treatment with miR-214-3p mimic. Global data analysis shows that Nu adiponectin has a role in microRNA-mediated post-transcription regulation, cell-cell interactions and chromatin remodeling as a survival gatekeeper.