Stigmasterol Ameliorates Obesity-Associated Insulin Resistance

Objective: This study aimed to investigate the effects of stigmasterol on obesity-related insulin resistance and to explore the underlying molecular mechanisms. Methods: Network pharmacology was used to screen the active components and key targets of Angelica sinensis that act on obesity and insulin resistance, and molecular docking was performed to assess the binding potential between stigmasterol and PPARγ. In cell experiments, an insulin-resistant 3T3-L1 adipocyte model was treated with different concentrations of stigmasterol and rosiglitazone. Lipid accumulation, oxidative stress indicators, and protein expression of the PPARγ pathway were measured. In animal experiments, high-fat diet-induced obese mice were administered stigmasterol and rosiglitazone, and serum metabolic parameters, histopathological changes, and hepatic oxidative stress and PPARγ pathway protein expression were measured. Results: Network pharmacology identified 90 overlapping targets, with PPARγ occupying a central position in the core network. Molecular docking indicated that stigmasterol showed good binding affinity for PPARγ. In insulin-resistant 3T3-L1 adipocytes, stigmasterol reduced intracellular TG and TC contents and lipid droplet accumulation, decreased ROS and MDA levels, increased the activities of CAT, GPx, and SOD, and upregulated the protein expression of PPARγ, the p-Akt/Akt ratio, and GLUT4 (p < 0.05). In obese mice, stigmasterol decreased the serum levels of fasting insulin, fasting blood glucose, HOMA-IR, TG, and TC, increased HOMA-ISI, reduced adipocyte size, alleviated hepatic steatosis, and lowered serum ALT and AST levels. Meanwhile, stigmasterol reduced hepatic ROS and MDA levels, restored antioxidant enzyme activities, and upregulated the protein expression of PPARγ, p-Akt/Akt, and GLUT4 in the liver (p < 0.05). Conclusion: Stigmasterol improved obesity-related glycolipid metabolic disorder and insulin resistance both in vitro and in vivo, and its mechanism involved activation of the PPARγ pathway and attenuation of oxidative stress.