Ramulus Mori (Sangzhi) alkaloids attenuate diet-induced obesity by modulating adipose tissue metabolic programs

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 metabolic activity, including thermogenic- and oxidative-related metabolic programs, has emerged as a promising 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), are clinically approved for T2DM treatment and exhibit multiple metabolic regulatory properties; however, their anti-obesity mechanisms remain incompletely understood. 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 body weight gain independent of food intake, improved glucose tolerance and insulin sensitivity, and alleviated dyslipidemia and hepatic steatosis. SZ-A also reduced the mass of multiple adipose depots and upregulated thermogenic regulators and beige adipocyte-associated markers in white adipose tissue (WAT). In brown adipose tissue (BAT), SZ-A partially restored HFD-impaired thermogenic features, accompanied by increased expression of uncoupling protein 1 (UCP1). In vitro, SZ-A directly promoted the expression of genes associated with adipocyte browning-related transcriptional features at the transcriptional level in differentiated 3T3-L1 adipocytes, supporting a cell-autonomous metabolic effect. Transcriptomic profiling of epididymal WAT (eWAT) revealed that SZ-A induced broad transcriptional remodeling, characterized by significant enrichment of fatty acid catabolism, β-oxidation, and lipid oxidative metabolism pathways, along with enrichment of brown adipocyte differentiation-related gene signatures. Collectively, these findings demonstrate that SZ-A exerts robust anti-obesity effects through coordinated regulation of adipose tissue metabolism, involving enhanced thermogenic-related molecular features in BAT and inguinal WAT (iWAT) and oxidative metabolic remodeling in visceral adipose tissue. Given its established clinical safety in T2DM, SZ-A represents a promising therapeutic candidate for adipose-based obesity and associated metabolic disorders.