SEMA3E promotes beige adipocyte differentiation and thermogenesis via β-catenin signaling in mice

Beige adipocytes play a key role in non-shivering thermogenesis. SEMA3E, a member of the class 3 semaphorin family, is involved in various pathological processes, but its role in adipocyte differentiation and thermogenesis remains unclear. Here, we found SEMA3E expression increased in inguinal white adipose tissue (iWAT) following cold exposure or β-adrenergic agonist CL316,243 stimulation. In vitro, loss- and gain-of-function experiments revealed that SEMA3E promoted beige adipocyte differentiation and enhanced thermogenic genes expression. In vivo, fat transplantation experiments indicated that SEMA3E promoted adipogenesis. Furthermore, adeno-associated virus (AAV)-mediated SEMA3E knockdown in iWAT impaired thermogenesis in mice exposed to cold or CL316,243. RNA-Seq analysis linked SEMA3E to mitochondrial oxidative phosphorylation, and its knockdown reduced mitochondrial respiration by downregulating respiratory chain components expression and lowering mitochondrial oxygen consumption rate. Mechanistically, gene set enrichment analysis suggested SEMA3E regulated beige adipocyte differentiation via the Wnt/β-catenin pathway. SEMA3E knockdown delayed β-catenin degradation, while inhibiting this pathway with IWR-1 rescued the suppressed differentiation and thermogenic genes expression. In conclusion, these findings highlight the crucial role of SEMA3E in beige adipocyte differentiation and thermogenesis.