Loss of histone methyltransferase Smyd3 triggers WAT browning and adaptive thermogenesis via enhancing PPARγ expression in a H4K20me3-dependent manner.

Adaptive thermogenesis driven by brown/beige adipose tissue has gained attention as a promising strategy for combating obesity. Histone methyltransferase SET and MYND Domain Containing 3 (Smyd3) is strongly associated with metabolic and cardiovascular diseases, however, its role in adaptive thermogenesis has not been well characterized. Here, we demonstrate that Smyd3 is abundant and closely involved in adipocyte thermogenic programming. However, genetic ablation of Smyd3 or pharmacological inhibition with the specific inhibitor EPZ031686 robustly enhanced adaptive thermogenesis in mice. Conversely, Smyd3 overexpression attenuated white adipose tissue (WAT) browning both in vivo and in vitro. Mechanistically, we found that loss of Smyd3 (pharmacological inhibition by EPZ031686, knockdown by Smyd3 siRNA and genetic ablation by Smyd3-KO mice) decreased the trimethylation of histone H4 lysine 20 (H4K20) within the promoter region of the transcription factor Peroxisome proliferator-activated receptor gamma (Pparg) gene and released the transcription suppression, thereby upregulating PPARγ expression, which initiates the transcription of thermogenic genes such as Uncoupling protein 1 (Ucp1), ultimately promoting the protein expression of UCP1 in the cytoplasm and triggering the adaptive thermogenesis program. Collectively, our findings identify Smyd3 as a potential therapeutic target for modulating adaptive thermogenesis. Pharmacological inhibition of Smyd3 with EPZ031686 represents a promising strategy to promote WAT browning and adaptive thermogenesis, offering a potential therapeutic avenue for combating obesity.