Augmenting Nrf2 signaling pathway promotes adipocyte differentiation from human embryonic stem cells

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor best regulating cellular defense mechanisms. However, its role in human adipocyte differentiation remains poorly understood. Here, we investigated the contribution of Nrf2 to adipocyte differentiation using an in vivo teratoma model, a straightforward assay for evaluating the differentiation potential of human embryonic stem cells (hESCs). We found that enhanced Nrf2 signaling, induced by KEAP1 gene deletion in hESCs, increased both the size and area of adipocytes within teratomas. Quantitative transcriptomic analysis of teratomas (TeratoScore) and the Ingenuity Pathway Analysis indicated activation of an adipogenesis-related signaling network, as evidenced by increased expression of FABP4, PPARG, ADIPOQ, and CEBPA in KEAP1-knockout teratomas. Stepwise in vitro differentiation of hESCs into adipocytes further supported a pro-adipogenic role for Nrf2, as shown by increased lipid-droplet accumulation. Notably, we identified PAX3 as a transcriptional target associated with Nrf2 activation, suggesting a potential link between Nrf2 signaling and adipogenic regulation. Together, these findings reveal a previously underappreciated role for Nrf2 in human adipogenesis.