Puerarin Attenuates Insulin Resistance by Inhibiting Endoplasmic Reticulum Stress and Suppresses Inflammation by Modulating the JNK and IKKβ/NF‐κB Pathways in Epididymal White Adipose Tissue of Mice on a High‐Fat Diet

Scope Obesity is associated with insulin resistance (IR), which is characterized by endoplasmic reticulum (ER) stress in multiple organs. ER stress in adipose tissue causes metabolic disturbances and activates inflammatory signaling pathways. Puerarin, an isoflavone extracted from Pueraria lobata , exhibits antioxidant, anti‐inflammatory, and antidiabetic effects. This study explores the potential mechanisms underlying puerarin's role in mitigating insulin resistance in high‐fat diet (HFD)‐induced obese mice. Methods and results In this study, insulin resistant in mice is induced by a high‐fat diet, followed by treatment with puerarin. The results demonstrate that puerarin effectively attenuates insulin resistance, including weight loss, improvement of glucose tolerance and insulin sensitivity, and activation of insulin signaling pathway. Additionally, puerarin administration suppresses ER stress by down‐regulation of ATF6, ATF4, CHOP, GRP78 expressions in epididymal white adipose tissue (eWAT), along with decreased phosphorylation IRE1α, PERK, and eIF2α. Furthermore, puerarin exerts anti‐inflammatory effects by inhibiting JNK and IKKβ/NF‐κB pathways, leading to reduction of TNF‐α and IL‐6. Conclusion These findings suggest that puerarin mitigates insulin resistance by inhibiting ER stress and suppressing inflammation through the JNK and IKKβ/NF‐κB pathways. This highlights the promising clinical application of puerarin in the treatment of insulin resistance.