Transient SUMOylation Inhibition In Human Pre-adipocytes Stably Imprints a Transcriptional Beiging Fate

Adaptive thermogenesis, or beiging, involves the conversion of energy-storing white adipocytes into energy-dissipating beige adipocytes, enabling physiological adaptation to environmental stressors such as hypothermia. While white and beige adipocytes share a largely similar transcriptome, this identity shift requires significant transcriptional and epigenetic reprogramming. However, the molecular mechanisms governing this transition remain incompletely understood. Here, we identify SUMOylation as a critical repressor of adipocyte beiging. Using the small-molecule SUMOylation inhibitor TAK-981, we demonstrate that transient SUMOylation inhibition primes human adipocytes to express beiging genes including UCP1 and induce mitochondrial uncoupling in a rosiglitazone-dependent manner. Furthermore, SUMOylation suppresses both the de novo differentiation of human adipose stem cells into beige adipocytes and the transdifferentiation of mature white adipocytes into beige cells. Mechanistically, TAK-981 modulates the cAMP-PKA-p38 signaling axis, ultimately affecting downstream transcriptional programs under the control of PPARG and PPARA enhancers. Our findings establish SUMOylation as a fundamental barrier to white-to-beige adipocyte reprogramming and suggest that the pharmacological combination of PPARG partial agonists with TAK-981 could promote metabolically beneficial adipose tissue remodeling in clinical settings.