Efeito da administração de ativadores do Nrf2 no reparo tecidual de camundongos obesos

Abstract

Obesity is the excessive accumulation of fat in the body due to excess nutrients. This condition leads to physiological changes that compromise injury repair. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway can improve and accelerate the healing of these injuries. However, more studies are needed to understand the relationship between this pathway and injury repair. The objective of this project was to evaluate the effect of Nrf2 activation through the activators hydroxytyrosol (HT) and dimethyl fumarate (DMF) in obese animals. Male C57BL/6 mice were fed daily with a control AIN-93M diet or a high-fat diet (50% energy from lipids). After 10 weeks, the animals were treated intraperitoneally with HT (1 mg/kg) and DMF (10 mg/kg). After 11 weeks, two total excisional lesions were created on the animals' backs. After 8 days of injury, the scars were collected. After 10 or 12 weeks of administration of the diets, the obese or obese+vehicle group showed a significant increase in body mass, the amount of epididymal fat, adipocyte diameter and glucose intolerance when compared to the control or control+vehicle group. Administration of DMF, but not HT, reduced the body mass of obese animals when compared to control groups (control+vehicle and obese+vehicle) after 12 weeks of diet. There was a significant reduction in adipocyte diameter in the obese+HT and obese+DMF groups after 12 weeks. However, there was no reduction in the amount of epididymal fat in both groups after 12 weeks. The administration of HT or DMF did not alter the effects of a high-fat diet on glucose intolerance, but only the administration of DMF reduced serum glucose levels. Administration of a high-fat diet increased serum levels of insulin, triglycerides, cholesterol and HDL cholesterol after 12 weeks. Administration of a high-fat diet induced steatosis in the animals' liver after 12 weeks, and treatment with Nrf2 activators did not reverse this effect. However, administration of HT or DMF reduced the mRNA levels of genes associated with lipogenesis in the liver of animals fed a high-fat diet. The obese+vehicle group showed an increase in the lesion area and a reduction in the re-epithelialized area when compared to the control+vehicle group after 8 days (12 weeks of diet). The administration of HT or DMF accelerated the closure of skin lesions and their re-epithelialization when compared to the control+vehicle and obese+vehicle groups after 8 days of injury (12 weeks of diet). The obese+vehicle group showed a reduction in collagen fiber content when compared to the control+vehicle group after 8 days of injury (12 weeks of diet). However, the administration of HT or DMF reversed the effect of the high-fat diet on collagen deposition when compared to the control groups. Treatment with HT or DMF promoted the translocation and binding of Nrf2 to DNA in skin lesions of obese animals after 8 days of injury (12 weeks on diet). Furthermore, the administration of HT or DMF reduced the production of reactive oxygen species and lipid peroxidation in the lesion of obese animals after 8 days (12 weeks of diet). In conclusion, the administration of HT or DMF promoted the repair of skin lesions and attenuated some obesogenic parameters.