Pharmacological inhibition of SUMOylation recapitulates genetic hypoSUMOylation in the murine epididymal white adipose tissue

Abstract

SUMOylation plays a critical role in regulating cellular reprogramming and stem cell differentiation. Interestingly, while most studies suggest that SUMOylation constrains these processes, both in vitro and in vivo knockdown (KD) and knockout (KO) studies, as well as experiments employing SUMOylation inhibitors, have demonstrated that adipose tissue formation and adipocyte differentiation require an active SUMOylation pathway. This apparently positions adipose tissue as a bystander in the broader context of SUMOylation-regulated cell fate and identity. To address this in vivo, we investigated the effects of SUMOylation inhibition in mice using TAK-981, a pharmacological SUMOylation inhibitor. Our results indicate that mice treated with TAK-981 develop lipoatrophy, characterized by reduced adipose tissue, due to impaired expression of adipogenic genes. These findings provide evidence that SUMOylation is essential for fat accumulation in vivo. Furthermore, given that TAK-981 is currently under clinical evaluation for the treatment of solid tumors, our findings underscore the importance of considering potential unintended effects of SUMOylation inhibition on adipose tissue in patients.