Non-Sugar Sweetener\nRubusoside Alleviates Lipid Metabolism\nDisorder In Vivo and In Vitro by Targeting PPARγ/α, Lgals3,\nand Mknk2

Rubusosidea high-sweetened, nonsugar sweeteneris\nmainly extracted from Rubus chingii var. <i>suavissimus</i> (S. Lee) L. T. Lu or Rubus suavissimus S. Lee (Chinese sweet leaf tea).\nWe previously reported that rubusoside regulates lipid metabolism\ndisorder in Syrian golden hamsters on a high-fat diet (HFD). This\nstudy aimed to reveal the underlying mechanisms through which rubusoside\nalleviates lipid metabolism disorder in vivo and in vitro. First,\nwe analyzed the therapeutic properties of rubusoside in alleviating\nHFD-induced lipid metabolism disorder in C57BL/6J mice. Then, we analyzed\nthe adipogenic effect of rubusoside in normal and Lgals3/Mknk2-overexpressing\n3T3-L1 cells by exploring the mechanisms on peroxisome proliferator-activated\nreceptor-γ/α (PPARγ/α), galectin-3 (Lgals3),\nmitogen-activated protein kinase interacting serine/threonine kinase-2\n(Mknk2), p38 mitogen-activated protein kinase (p38MAPK), and extracellular\nregulated protein kinases 1/2 (ERK1/2) with RT-qPCR and Western blot.\nOur results showed a rubusoside-mediated reduction of HFD-induced\nweight gain, dyslipidemia, and decelerated hepatic steatosis and adipose\ntissue expansion in mice as well as improved adipogenesis in 3T3-L1\ncells. Mechanistically, rubusoside up-regulated the PPARγ/α\nexpression while down-regulating Lgals3 and Mknk2 expression in vivo\nand in vitro. Furthermore, rubusoside attenuated the adipogenic activity\nof PPARγ through increasing its site-specific phosphorylation\nmediated by p38MAPK and ERK1/2. Taken together, our findings suggest\nthat rubusoside alleviates lipid metabolism disorder through multiple\npathways and thus holds potential for future development.