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 the thermogenic capacity within adipose tissues has emerged as a promising therapeutic strategy to counteract obesity and its related metabolic complications. Ramulus Mori (Sangzhi) alkaloids (SZ-A), a natural alkaloid complex derived from Morus alba L. (mulberry twig), have been clinically approved for the T2DM treatment and exhibit multiple metabolic regulatory properties. However, the precise anti-obesity mechanisms of SZ-A remain largely unclear. In this study, male C57BL/6 mice were fed a high-fat diet (HFD) for 14 weeks to induce obesity and subsequently treated with SZ-A (200 or 600 mg/kg) for 6 weeks. SZ-A markedly attenuated HFD-induced weight gain independent of food intake, improved glucose tolerance and insulin sensitivity, and alleviated dyslipidemia and hepatic steatosis. Furthermore, SZ-A reduced adipose tissue mass and upregulated key thermogenic regulators and beige adipocyte markers in white adipose tissue (WAT). It also restored brown adipose tissue (BAT) thermogenic activity by enhancing uncoupling protein 1 (UCP1) expression. In vitro, SZ-A promoted the expression of thermogenic and mitochondrial biogenesis-related genes in 3T3-L1 adipocytes, facilitating a beige-like phenotype. Transcriptomic analysis revealed that SZ-A significantly activated fatty acid catabolism and oxidation pathways, along with enrichment in the brown adipocyte differentiation pathway. Collectively, these findings demonstrate that SZ-A exerts potent anti-obesity effects through the dual mechanism of promoting WAT browning and enhancing BAT thermogenesis. Given its established clinical safety in T2DM, SZ-A represents a promising therapeutic candidate for adipose-based obesity and associated metabolic disorders.