A licorice‑derived compound 2,3β‑dihydroxy‑11‑oxo‑olean‑12‑en‑30‑oic acid to treat obesity and type 2 diabetes in mice

Objective To evaluate the therapeutic potential of 2,3 β ‑dihydroxy‑11‑oxo‑olean‑12‑en‑30‑oic acid (GA-03), a novel derivative of glycyrrhetinic acid (GA), against obesity and type 2 diabetes (T2D), and to elucidate its mechanisms in regulating leptin signaling and lipid metabolism, thereby providing new strategies for the optimization and development of similar bioactive components derived from traditional Chinese medicine. Methods A drug discovery strategy was devised, featuring a chemical backbone inspired by the scarce and toxic natural product, celastrol. By comparing 3-dimensional structural similarity and natural abundances, GA was selected as a viable mimic scaffold. For in vivo experiments, high-fat diet (HFD)-induced T2D mice, ob/ob mice, and db/db mice were treated with GA-03 to evaluate its effects on obesity, hyperglycemia, leptin sensitivity and other metabolic parameters. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to assess metabolic homeostasis. The molecular analyses such as hematoxylin and eosin (H&E) staining, Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the molecular mechanisms underlying the observed effects of GA-03. Results GA-03 showed a moderate binding affinity to the Nur77 receptor. In T2D mice, GA-03 effectively reduced body weight, food intake, and blood glucose levels in a dose-dependent manner. GA-03′s appetite-suppressing effect was linked to the leptin signaling pathway, enhancing the effectiveness of leptin in reducing food intake and body weight without noticeable toxicity and ready availability. At doses ranging from 2 to 8 mg/kg, GA-03 conferred long-term stable regulation of body weight and blood glucose levels in HFD-induced T2D mice under identical animal intervention conditions. Conclusion These findings identify GA-03 as a promising therapeutic lead targeting obesity and hyperglycemia in T2D. The compound exerts its metabolic benefits via fine-tuning the leptin signaling pathway and rectifying disrupted lipid metabolism, highlighting the necessity of further investigation.