SUMOylation Restricts Adaptive Thermogenesis by Suppressing Beiging Gene Networks

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 transcriptional similarity, this identity switch still requires 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 inhibition of SUMOylation primes human adipocytes to express beiging genes including UCP1 and inducing 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 agonists with TAK-981 can promote metabolically beneficial adipose tissue remodeling in clinical settings.