摘要：SummaryInhibition of Notch signaling has been shown to induce white to beige transformation of adipocytes and reduce the risk of obesity in mice. However, it remains unknown whether the metabolic benefits of Notch inhibition are dependent on uncoupling protein 1 (UCP1)-mediated thermogenesis and evolutionarily relevant in other mammalian species. Here we report the effect of Notch inhibition in adipocytes of pigs, which lost the UCP1 gene during evolution. Notch inhibition using a γ-secretase inhibitor dibenzazepine (DBZ) promoted beige adipogenesis and mitochondrial biogenic gene expression in porcine adipocytes. Moreover, encapsulation of DBZ into poly(lactide-co-glycolide) nanoparticles enabled rapid cellular internalization and enhanced bioactivity to achieve sustained Notch inhibition, thereby inducing beige-specific gene expression and reducing subcutaneous adipose tissue expansion in pigs. These results demonstrate for the first time a role of Notch signaling in regulating adipose plasticity in large animals, highlighting the therapeutic potential of targeting Notch signaling in obesity treatment.Graphical AbstractDisplay OmittedHighlights•DBZ promotes beige adipogenesis and mitochondrial biogenesis in porcine adipocytes•Encapsulation of DBZ into NPs allows for efficient and sustained Notch inhibition•DBZ NPs induce upregulated beige-specific gene expression in porcine adipocytes•Local injection of DBZ NPs reduces subcutaneous adipose tissue expansion in pigsBiological Sciences; Physiology; Cellular Physiology; Cell Biology
