GW-9662, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor, impairs early embryonic development in zebrafish

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) functions as a nuclear transcription factor with primary roles in lipid and glucose metabolism and adipocyte differentiation. Despite intensive research in metabolic contexts, its role during early vertebrate development remains underexplored. Our study focused on understanding PPARγ's developmental role by using a PPARγ antagonist, GW-9662 (GW), in zebrafish embryos. We exposed embryos to GW from 6 hours post-fertilization (hpf) to 24 hpf and observed that the embryos were ventralized by 24 hpf. Western Blot and immunohistochemistry for PPARγ protein demonstrated that GW-mediated PPARγ inhibition may be localized within the embryos. Transcriptomic analysis revealed that exposure to GW led to dysregulation of multiple biological pathways, including cytoskeletal organization, lipid biosynthesis, and epithelial-to-mesenchymal transition (EMT). Immunohistochemistry further validated these findings, demonstrating increased lipid accumulation, cytoskeletal disruption, and altered EMT markers. Our findings suggest that while GW plays a crucial role in multiple physiological processes during early embryogenesis, further research is needed to examine if these impacts are mediated by PPARγ.