Ramulus Mori (Sangzhi) Alkaloids Attenuate Diet-Induced Obesity by Promoting White Adipose Browning and Enhancing Brown Fat Thermogenesis

Obesity is a chronic metabolic disorder characterized by excessive adipose accumulation and is closely associated with type 2 diabetes mellitus (T2DM), cardiovascular diseases, and metabolic dysfunction associated steatotic liver disease. Enhancing adipose thermogenic capacity has emerged as a promising strategy to counteract obesity. Ramulus Mori (Sangzhi) alkaloids (SZ-A), a natural alkaloid complex clinically approved for T2DM, exhibit multiple metabolic benefits, but their anti-obesity mechanisms remain unclear. Overall design: In this study, male C57BL/6 mice were fed a high-fat diet (HFD) for 14 weeks and subsequently treated with SZ-A (200 or 600 mg/kg) for 6 weeks. SZ-A markedly reduced HFD-induced weight gain independent of food intake, improved glucose tolerance and insulin sensitivity, and alleviated dyslipidemia and hepatic steatosis. SZ-A also decreased adipose tissue mass and upregulated key thermogenic regulators and beige adipocyte markers in white adipose tissue (WAT). In brown adipose tissue (BAT), SZ-A restored thermogenic activity by enhancing uncoupling protein 1 (UCP1) expression and improving tissue morphology. In vitro, SZ-A increased the expression of thermogenic and mitochondrial biogenesis–related genes in 3T3-L1 adipocytes, promoting a beige-like phenotype. Transcriptomic profiling further revealed activation of fatty acid catabolism, oxidation pathways, and enrichment of brown adipocyte differentiation signatures. Collectively, these findings demonstrate that SZ-A exerts potent anti-obesity effects through dual actions on WAT browning and BAT thermogenesis. Given its established clinical safety, SZ-A represents a promising therapeutic candidate for adipose-based obesity and metabolic disorders.