Expression and activity of NRF2 in aorta of mice with insulin resistance submitted to the caloric restriction

• Grant number: 17/26095-9
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): November 01, 2018
• Effective date (End): October 31, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal researcher: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Fernanda Helena Cardoso Minelli
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Obesity is an important cause of morbidity and mortality and is associated with an increased prevalence of chronic diseases, such as coronary disease, type 2 diabetes mellitus, and insulin resistance. Caloric restriction is considered an excellent intervention to counteract the deleterious effects associated with metabolic diseases in different species, from yeasts to mammals, but the mechanisms involved in its beneficial effects need to be further explored. Obesity is associated with increased generation of reactive oxygen species (ROS), which directly affects the cardiovascular system. The Nrf2 system regulates the transcription of many antioxidant and cytoprotective genes, such as catalase, glutathione peroxidase, and superoxide dismutase. Decreased Nrf2 activity contributes to increased oxidative stress and mitochondrial dysfunction, which leads to endothelial dysfunction and insulin resistance. Considering that increased ROS generation promotes vascular dysfunction and that Nrf2 is an important regulator of the redox system, protecting against oxidative stress-induced damage, our hypothesis is that caloric restriction in obese mice positively regulates the Nrf2 antioxidant system, decreasing ROS accumulation and improving vascular function. Mice will receive either a standard control diet or a hyperlipidemic diet (hight fat diet, HFD - for obesity induction) for 18 weeks. Subsequently, they will undergo a 30% reduction in the same diet for 30 days, corresponding to an intervention in the caloric intake - caloric restriction. Vascular function will be evaluated in endothelium-intact aortic rings, and Nrf2 activity/signaling will be investigated by assays evaluating gene and protein expression/activity of components of the Nrf2 pathway.