Background and purposeSwertiamarin (STM), a secoiridoid glycoside from Swertia chirayita (Roxb.) H. Karst, has been shown to decrease body weight, blood glucose, and blood lipids by inhibiting adipose tissue hypertrophy. However, the underlying mechanisms remain unclear. In particular, adipose thermogenesis is a novel avenue for exploring the pharmacological effects of STM. We aim to investigate the efficacy of STM on type 2 diabetes mellitus (T2DM), with a focus on underlying mechanisms, particularly the activation of ADRB3/UCP1 thermogenic signaling pathways.MethodsT2DM model was established by a high-fat diet (HFD) and streptozotocin (STZ) in C57BL/6J male mice. Mice were given to either 100 or 200 mg/kg/day of STM, or 200 mg/kg/day of metformin via intragastric administration for 7 weeks. In vitro, 3T3-L1 cells were differentiated into adipocytes. Molecular markers related to ADRB3-UCP1 signals, lipolysis, and mitochondrial function were detected.ResultsSTM-treated diabetic mice showed a reduction of body weight, fat mass, and blood glucose/lipids and an improvement in insulin sensitivity. Bioinformatics analysis indicated STM promoted lipid metabolism and mitochondrial function, features by closely associated with adipose thermogenesis. STM upregulated the lipolysis-related genes and p-HSL protein in inguinal subcutaneous white adipose tissue (igSWAT) and brown adipose tissue (BAT). STM-treated mice processed a more active energy metabolism. Additionally, the ADRB3-UCP1 signals, mitochondrial-related genes, and oxidative phosphorylation were improved in igSWAT and BAT. In vitro, we found STM interacted with ADRB3, increasing glucose uptake, glycerol release, ADRB3-UCP1 signals, p-HSL expression, mitochondrial content, oxidative phosphorylation complex expression with improved mitochondrial Δψm, as well as reduced lipid accumulation in adipocytes. All these effects were reversed upon ADRB3 inhibition.ConclusionThis study identifies a previously unknown role of STM activating ADRB3/UCP1 signals in adipose tissue, suggesting a potential strategy for treating T2DM.