Non-Sugar Sweetener Rubusoside Alleviates Lipid Metabolism Disorder In Vivo and In Vitro by Targeting PPARγ/α, Lgals3, and Mknk2

Rubusoside─a high-sweetened, nonsugar sweetener─is mainly extracted from <i>Rubus chingii</i> var. <i>suavissimus</i> (S. Lee) L. T. Lu or <i>Rubus suavissimus</i> S. Lee (Chinese sweet leaf tea). We previously reported that rubusoside regulates lipid metabolism disorder in Syrian golden hamsters on a high-fat diet (HFD). This study aimed to reveal the underlying mechanisms through which rubusoside alleviates lipid metabolism disorder in vivo and in vitro. First, we analyzed the therapeutic properties of rubusoside in alleviating HFD-induced lipid metabolism disorder in C57BL/6J mice. Then, we analyzed the adipogenic effect of rubusoside in normal and Lgals3/Mknk2-overexpressing 3T3-L1 cells by exploring the mechanisms on peroxisome proliferator-activated receptor-γ/α (PPARγ/α), galectin-3 (Lgals3), mitogen-activated protein kinase interacting serine/threonine kinase-2 (Mknk2), p38 mitogen-activated protein kinase (p38MAPK), and extracellular regulated protein kinases 1/2 (ERK1/2) with RT-qPCR and Western blot. Our results showed a rubusoside-mediated reduction of HFD-induced weight gain, dyslipidemia, and decelerated hepatic steatosis and adipose tissue expansion in mice as well as improved adipogenesis in 3T3-L1 cells. Mechanistically, rubusoside up-regulated the PPARγ/α expression while down-regulating Lgals3 and Mknk2 expression in vivo and in vitro. Furthermore, rubusoside attenuated the adipogenic activity of PPARγ through increasing its site-specific phosphorylation mediated by p38MAPK and ERK1/2. Taken together, our findings suggest that rubusoside alleviates lipid metabolism disorder through multiple pathways and thus holds potential for future development.