Modulation of Cuproptosis Pathway Genes (DLAT, FDX1) and Antioxidant Enzyme Activities in Obese Mice in Response to Quercetin and Calorie Restriction

Cuproptosis is a new mode of cell death that is closely related to mitochondrial stress. The purpose of this study is to investigate the amount of copper, copper-associated genes DLAT and FDX1 oxidative stress (OS) status in obesity. Since there is a close relationship between OS and cuproptosis, evaluating the effect of various strategies to reduce OS, including quercetin (QUER) and caloric restriction (CR), is another goal of this study. In this study, 30 male BALB-C mice aged 8 weeks and weighing 25 g, including the groups receiving normal diet (ND), ND with QUER (15 mg/kg, IP) and CR, a high-fat diet (HFD) with the QUER, CR or a combination of both were used. The activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione reductase (GR), amount of copper in the liver and kidney tissues, and expression of DLAT and FDX1 genes were measured in all studied groups. The amount of copper in the liver and kidney tissue as well as the expression of FDX1 and DLAT in the HFD group increased significantly compared with the ND group. QUER, CR or their combination could significantly reduce the amount of copper as well as the expression of FDX1 and DLAT in liver and kidney tissues. QUER and CR, also significantly increased the activity of GR, SOD and GPX in serum, liver, and kidney tissues. Based on the results, QUER, CR and especially the simultaneous use of both, was able to reduce the amount of copper and its related cuproptosis. These effects may reduce cuproptosis-associated cell death. Therefore, the use of antioxidants and CR may be a promising solution to protect the human body against the effects of cuproptosis in conditions like obesity.