ETS2-Driven PRDM16 transcription activates the IRS-1–PI3K/Akt–mTOR Axis to promote thermogenesis in adipocytes

Background Brown adipose tissue adaptive thermogenesis is regulated by a complex signaling network. PRDM16 serves as a core regulator of the thermogenic program, and previous studies have demonstrated that it promotes thermogenesis through multiple pathways. In previous study, adipocyte-derived ETS2 promotes thermogenesis by regulating PRDM16 transcription; however, how PRDM16 within this axis influences thermogenesis remains to be elucidated. Objective This study aims to clarify how PRDM16, as a downstream effector of ETS2, influences adipocyte thermogenesis, and to identify the signaling pathways involved. Methods Using adipocyte-specific Ets2 knockout (Ets2KO) mouse model and primary adipocytes, combined with lentivirus-mediated Prdm16 knockdown and overexpression, we analyzed the effects of ETS2 and PRDM16 on downstream signaling pathways. The phosphorylation levels of key nodes in the IRS-1–PI3K/Akt–mTOR pathway were detected by Western blot. Ets2KO mice and cells were treated with the mTOR-specific agonist MHY1485 to evaluate the causal role of this pathway in thermogenic function. Results In brown/beige adipose tissues of Ets2KO mice, we observed a significant reduction in IRS-1, accompanied by marked inhibition of the phosphorylation of PI3K/Akt and downstream mTOR signaling, which preceded changes in thermogenic gene expression. Knockdown of Prdm16 in wild-type cells reduced the expression of UCP-1, whereas Prdm16 overexpression partially restored the activity of this pathway in Ets2-deficient cells. Interestingly. Treatment with MHY1485 significantly restored thermogenic gene expression and cold tolerance in Ets2KO mice, confirming that inhibition of mTOR signaling is a key downstream event mediating the phenotype resulting from Ets2 deletion. Conclusion This study reveals a novel function of the ETS2–PRDM16 axis in adipocytes: regulating thermogenesis by maintaining the activity of the IRS-1–PI3K/Akt–mTOR signaling pathway. This effect is independent of the classical function of PRDM16, indicating that PRDM16 possesses a dual regulatory mechanism. This finding expands our understanding of the thermogenic signaling network in adipose tissue and provides a new perspective for the treatment of metabolic diseases.Figure_1