Western style diet-induced lipid peroxidation is associated with upregulation of p66shc signaling
Authors: Li Jessica , Wei Xingyu , Tong Shiwei , Guo Yuliang , He Huamei 
Published: May 2023

Background: Obesity is one of the leading risks for death worldwide due to numerous comorbidity diseases. One of the primary causes for obesity and related metabolic disorders is related to the western-style (high-fat high-sucrose) diet (HFHSD). Animals fed a HFHSD developed glucose intolerance, dyslipidemia, and liver, heart, kidney, and skeletal muscle damages. However, whether their damages are related to the same mechanism remains unclear. Additionally, whether HFHSD could induce brain and skin damages is still unknown. As adaptor protein p66Shc plays a crucial role in oxidative stress, which plays a pivotal role in the development and progression of multiple diseases, therefore, we assessed p66shc signaling and oxidative stress in multiple organs (brain, heart, liver, kidney, skeletal muscle, and skin) of the mice subjected to metabolic challenges—sustained consumption of a HFHSD. Methods: 20 three-week-old male C57BL/6 mice were fed a normal chow diet (CD) or a HFHSD (mixture of 53% basic feed, 37% sucrose, 10% lard) for 18 weeks. After overnight fasting, the body weight, abdominal circumference, and body mass index (BMI) were measured. Whole blood was collected and centrifuged to separate the serum. The serum glucose and insulin level were measured using the immobilized glucose oxidase method and enzyme-linked immunosorbent assays. The insulin resistance was evaluated by the homeostasis model assessment. Serum total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and leptin were determined enzymatically using commercially available kits. The brain, heart, liver, kidney, skeletal muscle, and skin were collected to determine p66Shc mRNA expression, p66Shc phosphorylation, H2O2, and lipid peroxidation marker malondialdehyde (MDA) using real-time quantitative PCR, Immunoblotting, H2O2 and MDA Assay Kits, respectively. Results: 18-week HFHSD increased mouse body weight, abdominal circumference, BMI, fasting blood glucose levels, fasting insulin levels, insulin resistance, TC, TGs, LDL, HDL, and leptin by 1.6, 1.3, 1.2, 1.6, 3.1, 4.1, 2.6, 3.6, 2.4, 2.0, and 1.4 times, respectively, indicating that 18-week HFHSD causes mouse hyperinsulinemia. Interestingly, p66Shc mRNA expression, p66Shc phosphorylation were significantly increased in heart, liver, kidney, and skeletal muscle from mice fed a HFHSD, accompanied by increased H2O2 and MDA levels. p66Shc mRNA expression and p66Shc phosphorylation in brain and skin of mice fed a HFHSD, however, were not different from those in mice fed a ND. Surprisingly, H2O2 and MDA levels in those tissues also showed no differences between the mice fed a HFHSD and a ND. Conclusion: Our results support that western style diet-induced lipid peroxidation in multiple organs is closely associated with upregulation of p66shc signaling. Pharmacological suppression of p66shc signaling could potentially prevent HFHSD-induced organ oxidative damage. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.