The aim of this study was to investigate whether umbelliferone (Umb) could attenuate insulin resistance in unpredictable chronic mild stress (CUMS)-induced rats. Behavioral changes were evaluated through sucrose preference test (SPT), openfield test, forced swimming test, and tail suspension test (TST), suggesting that Umb (20 and 40 mg/kg) could effectively improve depression symptoms. Oral glucose tolerance test and serum insulin indicated that Umb attributed to the control of blood glucose levels. The phosphorylation of insulin receptor, insulin receptor substrate (IRS)21, glycogen synthase kinase-3b, PI3K, and Akt was increased in Umb (20 and 40 mg/kg) treatment according to Western blot analysis. Taken together, the current results suggested the ameliorative effect of Umb against insulin resistance in the CUMS-induced rats. V C 2016 IUBMB Life, 68(5): [403][404][405][406][407][408][409] 2016