Transcription factor ETS2 activates Prdm16 to drive adipocyte thermogenesis via the PRDM16–PGC-1α–UCP1 Axis

Background Brown/beige adipose tissue plays a key physiological role in energy expenditure, representing a promising therapeutic target against obesity and metabolic disorders. While previous studies suggest transcription factor ETS2 is critical for adipocyte function, its molecular regulatory mechanisms in Brown/beige adipose tissue thermogenesis and the browning process remain poorly understood. Objective This study aims to investigate the roles of transcription factor ETS2 in the function of brown/beige adipose tissue and elucidate the molecular mechanisms of ETS2 in the thermogenic function of brown/beige adipose tissue and "browning" process. Methods Adipocyte-specific Ets2 knockout (Ets2KO) mice and primary adipocytes were generated in this study to assess thermogenic responses following cold exposure (4°C) and stimulation with the β3-adrenergic agonist CL316243. The expression of thermogenic genes and mitochondrial biogenesis were evaluated using qPCR, Western blot, and transmission electron microscopy. Dual-luciferase reporter assays and chromatin immunoprecipitation were performed to verify the direct binding of ETS2 to the promoter of downstream target genes and its role in transcriptional activation. Results Adipocyte-specific deletion of Ets2 significantly suppressed the thermogenic response induced by cold exposure and CL316243 stimulation, as evidenced by a more pronounced decrease in core body temperature, markedly reduced expression levels of Ucp1, Pgc-1α, and Prdm16, and a decline in both mitochondrial number and cristae structure. Mechanistic studies revealed that ETS2 directly binds to the promoter region of Prdm16, thereby activating its transcription. Overexpression of PRDM16 partially rescued the downregulation of UCP1 and PGC-1α caused by Ets2 deletion. In the adipose tissue of Ets2KO mice, the activity of the PRDM16–PGC-1α–UCP1 transcriptional axis was comprehensively suppressed. Conclusion ETS2 as a direct transcriptional activator of PRDM16, driving adipocyte thermogenesis and mitochondrial biogenesis by regulating the PRDM16–PGC-1α–UCP1 axis. This finding reveals a novel transcriptional regulatory hierarchy in brown/beige adipose tissue thermogenesis and provides a potential molecular target for intervention in obesity.Figure_1Figure_2