Isoliquiritigenin (ILG), a chalcone from Glycyrrhiza uralensis, has various biological properties. ILG markedly inhibited inflammation, but the effects on the brain inflammation and insulin resistance induced by high-fat diet (HFD) are still unknown, so our study intended to investigate its effect on cognitive dysfunction induced by HFD and the relevant mechanisms. ICR mice were treated with HFD diet for 8 weeks to induce peripheral insulin resistance prior to being intervened with rosiglitazone, ILG (30, 60 mg/kg). 4 weeks later, Morris Water Maze (MWM) was used to assess the learning and memory, the insulin resistance index was measured, and the brain inflammation cytokines (IL-1 beta, TNF-alpha) were assessed. Meanwhile, the p-JNK, p-IRS Ser(307) protein expressions in the hippocampus were also detected using the western blot to explore the corresponding mechanisms. Our results suggested that ILG could significantly alleviate the cognitive impairments in the MWM test and attenuate peripheral insulin resistance. The IL-1 beta, TNF-alpha levels declined with the administration of ILG, meanwhile the p-IRS Ser(307) expression decreased with the inhibition of p-JNK. In conclusion, ILG could improve the spatial learning and memory lesions induced by HFD via the inhibition of TNF-alpha/JNK/IRS pathway. (C) 2015 Elsevier Inc. All rights reserved.