Nrf2 activation by hydroxytyrosol and dimethyl fumarate ameliorates skin tissue repair in high‐fat diet‐fed mice by promoting M2 macrophage polarization and normalizing inflammatory response and oxidative damage

Abstract Hydroxytyrosol (HT) or dimethyl fumarate (DMF), activators of nuclear factor erythroid 2‐related factor 2 (Nrf2), may reduce obesity in high‐fat diet (HFD)‐fed animals; nevertheless, the role of these activators on skin tissue repair of HFD‐fed animals was not reported. This study investigated whether HT or DMF could improve skin wound healing of HFD‐fed obese animals. Mice were fed with an HFD, treated with HT or DMF, and full‐thickness skin wounds were created. Macrophages isolated from control and obese animals were treated in vitro with HT. DMF, but not HT, reduced the body weight of HFD‐fed mice. Collagen deposition and wound closure were improved by HT or DMF in HFD‐fed animals. HT or DMF increased anti‐inflammatory macrophage phenotype and protein Nrf2 levels in wounds of HFD‐fed mice. Lipid peroxidation and protein tumor necrosis factor‐α levels were reduced by HT or DMF in wounds of HFD‐fed animals. In in vitro, HT stimulated Nrf2 activation in mouse macrophages isolated from obese animals. In conclusion, HT or DMF improves skin wound healing of HFD‐fed mice by reducing oxidative damage and inflammatory response. HT or DMF may be used as a therapeutic strategy to improve the skin healing process in individuals with obesity.