Objective To investigate the role of peroxisome proliferators-activated receptors γ (PPARγ) in hight-fat induced insulin resistance by regulating microRNA (miRNA)-223. Methods The rat model of type 2 diabetes mellitus was established by feeding high-fat diet and treated with pioglitazone. Serum miRNA-223, blood glucose and 4 inflammatory factors (interleukin[IL]-1β, IL-6, IL-8, and tumor necrosis factor α[TNF-α]) in type 2 diabetes mellitus rats before and after treatment were detected by quantitative polymerase chain reaction (qPCR), glucose oxidase peroxidase and enzyme-linked immunosorbent assay. In a model of insulin resistance in HepG2 cells induced by palmitic acid, the levels of PPARγ or miRNA-223 were upregulated or inhibited, and the level of cellular glucose absorbtion, expression of cell glucose transporters (glucose transporters 1, 2, 4; insulin receptor substrates 1, 2) and miRNA-223 level were detected by Cell glucose absorption experiment, Western blotting and qPCR, respectively. Results Compared with that before pioglitazone treatment, the fasting blood glucose level of rats and the expression of serum inflammatory factors (IL-1β, IL-6, IL-8, and TNF-α) were significantly decreased and the level of serum miRNA-223 was significantly increased after 7 d of pioglitazone treatment (all P<0.001). After 24-h treatment with palmitic acid, the expression of PPARγ protein, miRNA-223 level and glucose absorption level of HepG2 cells were significantly decreased (all P<0.05). Upregulation of PPARγ protein could ameliorate the decrease of cellular glucose absorption induced by palmitic acid and increase the levels of miRNA-223 and inflammatory factors (all P<0.05). Inhibition of PPARγ expression resulted in decreased glucose absorption (P<0.05) and decreased miRNA-223 level (P<0.05), but there was no regulatory effect on the level of inflammatory factors in normal cells. Overexpression of miRNA-223 could improve the palmitic acid-induced decrease of glucose absorption and the increase of inflammatory factors (both P<0.05), as well as up-regulate the expression of glucose transporters (glucose transporters 1, 4) and insulin receptor substrate 1 (all P<0.05). Inhibition of miRNA-223 had an opposite effect of overexpression of miRNA-223 on the level of PA-induced cellular glucose uptake and expression of glucose transporter protein 1, glucose transporter protein 4, and insulin receptor substrate 1 (all P<0.05). However, overexpression or inhibition of miRNA-223 did not affect the expression of PPARγ. Conclusion PPARγ can improve glucose absorption of insulin resistance cells induced by high fat by regulating miRNA-223.