Background: Resistin is associated with insulin resistance, and determining its developmental and molecular mechanisms may help the development of novel treatments. MicroRNAs (miRNAs) are involved in many physiological and pathological processes as negative regulators. However, it remains unclear whether miRNAs play a role in resistin-induced insulin resistance. We performed mouse liver miRNA microarrays to analyze the differences in expression between resistin-treated and control mice. Resistin upregulated miR-145 both in vivo and in vitro. Therefore, we aimed to study whether miR-145 played a role in resistin-induced insulin resistance. Methods and results: We transfected HepG2 cells, and used miR-145 mimics and inhibitors to assess the role of miR-145 in resistin-induced insulin resistance. The overexpression of miR-145 inhibited glucose uptake in HepG2 cells, diminished the phosphorylation of Akt and IRS-1, and induced insulin resistance in hepatocytes. Next, a study of transcriptional regulation revealed that p65 was essential for the upregulation of miR-145 by resistin, and chromatin immunoprecipitation (ChIP) confirmed that p65 could bind to the promoter region of miR-145. Conclusion: miR-145 plays a role in the development of resistin-induced insulin resistance via the p65 pathway. (C) 2014 Elsevier Inc. All rights reserved.