Besides its well -established oncosuppressor activity, the role of p53 in regulating metabolic pathways has been recently identified. Nevertheless, the function of p53 with respect to insulin resistance appears highly controversial. To address this issue, we investigated the expression of p53 in experimental model of insulin resistance. Then we used activator (nutlin-3 alpha) and inhibitor (pifithrin-alpha, PFT-alpha) of p53 in HepG2 cell. Here we showed that p53 protein level was decreased in the hepatic tissue of high-fat diet induced insulin resistance mice, genetically diabetic ob/ob mice and palmitate (PA) treated HepG2 cells. And high expression of phosphor-p38, ERK1/2 and nuclear factor kappa B (NF-kappa B) p65 accompanied with low expression of p53. But activation of p53 with nutlin-3a prevented PA-induced reduction of glucose consumption and suppression of insulin signaling pathways. At the same time, nutlin-3a downregulated the activation of NF-kappa B, p38 and ERK1/2 pathways upon stimulation with PA. In contrast, inhibition of p53 with PFT-a decreased glucose consumption and suppressed insulin signaling pathway. Furthermore, PFT-alpha activated NF-kappa B, p38 and ERK1/2 pathways in HepG2 cells. Overall, these results suggest that p53 is involved in improving insulin sensitivity of hepatic cells via inhibition of mitogen-activated protein kinases (MAPKs) and NF-kappa B pathways. (C) 2017 Elsevier Inc. All rights reserved.