SETD7 depletion enhances white adipose browning and ameliorates metabolic disorders in obese mice

Abstract Obesity, a major global health challenge associated with metabolic and cardiovascular disorders, has drawn increasing attention to the therapeutic potential of white adipose tissue (WAT) browning. Although the lysine methyltransferase SETD7 has been implicated in various cardiovascular and metabolic diseases, its role in adipose thermogenesis remains unclear. Here, we reported that SETD7 was upregulated in inguinal WAT (iWAT) of obese mice and was primarily localized to mature adipocytes. Setd7 knockdown ( Setd7 ⁺/⁻ ) mice exhibited enhanced thermogenic gene expression and iWAT browning upon cold exposure or β3-adrenergic stimulation, whereas thermogenic activity in brown adipose tissue (BAT) remained largely unaffected. In vitro, SETD7 knockdown did not alter adipogenesis but potently augmented thermogenic capacity in beige adipocytes, while SETD7 overexpression exerted the opposite effect. Mechanistically, RNA-Seq analysis revealed that SETD7 deficiency upregulated Adcy7 transcription, leading to increased Sirt1 levels and enhanced Creb1 phosphorylation, thereby activating the thermogenic program. Notably, Setd7 ⁺/ – mice resisted high-fat diet (HFD)-induced obesity, exhibiting reduced weight gain, elevated energy expenditure, and improved metabolic health. Together, these findings identify SETD7 as a negative regulator of iWAT thermogenesis and suggest that targeting SETD7 may represent a promising strategy for combating obesity.