Taraxasterol Acetate Attenuates TNF-α-Induced Insulin Resistance via Regulation of Insulin Signaling, Inflammation, and Lipid Metabolism in 3T3-L1 Cells

Abstract Insulin resistance, obesity, and type 2 diabetes mellitus (T2DM) are interrelated metabolic disorders with rising global prevalence. Triterpenes, known for their diverse pharmacological properties, have shown potential in improving insulin sensitivity and exerting antidiabetic and antiobesity effects. This study evaluated the effects of taraxasterol acetate (TXA), a pentacyclic triterpene isolated from Eupatorium ballotaefolium, on TNF-α-induced insulin resistance and lipolysis in mature 3T3-L1 adipocytes. TXA significantly enhanced glucose uptake in insulin-resistant adipocytes by promoting GLUT4 translocation by activating the IRS-1/PI3K/Akt signaling pathway and upregulating AMPK expression. TXA also inhibited NF-κB and JNK signaling, reducing inflammation and mitigated oxidative stress by decreasing intracellular reactive oxygen species (ROS) levels and enhancing antioxidant enzyme activity, including superoxide dismutase (SOD) and catalase (CAT). Moreover, TXA normalized adipokine secretion by increasing leptin and adiponectin levels, and promoted lipid accumulation through the modulation of PPARγ, HSL, ATGL, and Perilipin expression. TXA further improved lipid metabolism by upregulating fatty acid β-oxidation genes (ACOX1, CPT1b) and supported mitochondrial function by enhancing PGC-1α and TFAM expression. Collectively, these findings demonstrate that TXA mitigates TNF-α-induced insulin resistance by improving insulin signaling, suppressing inflammation and oxidative stress, and improving lipid and mitochondrial metabolism. These results suggest that TXA is a promising therapeutic candidate for the prevention and treatment of insulin resistance and related metabolic disorders.