Anti-diabetic effect of hesperidin on palmitate (PA)-treated HepG2 cells and high fat diet-induced obese mice

The present study examined the relationship between the anti-diabetic effect of hesperidin (HES) and the differential gene expression in HES treated high fat diet (HFD)-induced obese mice. Based on the glucose uptake assay, the treatment of HES restored the glucose uptake to control level in an insulin-independent manner in PA-treated HepG2 cells. Western blot analysis confirmed that the treatment of HES increased the insulin-stimulated phosphorylation of Akt and GSK3β in insulin-resistant PA-treated HepG2 cells. HFD-induced obese mice treated with HES significantly reduced serum insulin, blood glucose, and homeostatic model assessment for insulin resistance (HOMA-IR) values. In addition, both glucose tolerance and insulin tolerance were significantly improved to normal level by HES in HFD-induced obese mice. RNA sequencing analysis disclosed that the expression levels of up-regulated 12 genes and down-regulated 6 genes related to insulin signaling and glucose metabolism were restored to normal level by HES in the liver of HFD-induced obese mice. A protein–protein interaction (PPI) network was constructed via search tool for the retrieval of interacting genes/proteins (STRING) analysis, and Eno1, Pik3cd, Hk2, Trib3, Myc, Nos3, Ppargc1a, and Igf2 were located in the functional hubs of the PPI network of glucose metabolism. Furthermore, Western blot analysis confirmed that HES improved insulin sensitivity and glucose homeostasis by normalizing the expression levels of hexokinase-II, enolase-1, and PI3 kinase p110δ to normal level. The overall results suggest that HES possess a potential anti-diabetic effect by normalizing the expression levels of the insulin signaling and glucose metabolism related genes which were perturbed in the liver of HFD-induced obese mice.