The role of physical exercise on ROCK protein pathway, and lipogenic regulation and gluconeogenesis in the liver of aged rats

Author(s)

Vitor Rosetto Muñoz

• Document type: Doctoral Thesis
• Press: Limeira, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas
• Defense date: 2021-09-09

Examining board members

José Rodrigo Pauli; Fernando Moreira Simabuco; Luiz Osório Leiria; Adriana Souza Torsoni; João Paulo Gabriel Camporez

• Advisor: José Rodrigo Pauli

Abstract

Aging is a natural biological process that is associated with an increased risk of developing metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). This risk increases in sedentary subjects and with expressive adiposity. Therefore, the identification of the cause or triggering factors of these metabolic disorders and liver disease can help healthcare professionals to control or prevent the problem. The ROCK protein has been promising to act on the insulin pathway, interfering metabolism, however, its effect on liver tissue has not been fully elucidated. The aim of this study was to investigate the effects of aerobic exercise on the ROCK protein and its impact on insulin signaling, lipogenesis, and hepatic gluconeogenesis in aged rodents. Experiments involving young and old Wistar and Fischer rats, and C57BL/6J mice were conducted. Experiments with a pharmacological ROCK inhibitor (Y-27632) were also carried out with mice. Seeking to mimic some metabolic disturbances seen with advancing age, additional experiments inducing low-grade inflammation (lipopolysaccharides), fibrosis (carbon tetrachloride), hyperinsulinemia (Slc2a4+/- mice), and obesity (Swiss and Ob/Ob mice) were performed. Finally, experiments with hepatic cells allowed us to assess the insulin signaling pathway in situations of ROCK inhibition and overexpression, and with palmitate and insulin stimuli. The results show that aging is associated with an increase in ROCK activity in the liver, regardless of the adiposity degree of the rodents. Furthermore, the increase in ROCK activity was accompanied by impaired insulin signaling and increased proteins involved in the processes of hepatic gluconeogenesis and lipogenesis, with consequent hyperglycemia and greater hepatic fat accumulation. These dysmetabolic manifestations were also seen in obese mice (Swiss and Ob/Ob), hyperinsulinemic mice (Slc2a4+/- ), and under conditions of liver fibrosis or exposure to lipopolysaccharides. On the other hand, it is verified in different strains of aged rodents and in those exposed to different treatments that aerobic exercise was able to decrease ROCK activity, improve insulin signal transduction, and this was accompanied by a reduction in key proteins related to gluconeogenesis and lipogenesis pathway in the liver. Similar effects were observed through pharmacological inhibition of ROCK (Y-27632) in C57BL/6J mice or in cell culture. In cell experiments, inhibition of ROCK potentiated the insulin signaling pathway, and overexpression of ROCK1 increased the content of lipogenic protein SREBP1c. In conclusion, this is the first study to demonstrate that increased ROCK activity is associated with impaired insulin signaling and increased gluconeogenesis and lipogenesis processes in the liver tissue of aged rodents. On the other hand, aerobic physical exercise was able to suppress ROCK activity and improve insulin signal transduction, and this was accompanied by a reduction in gluconeogenesis and lipogenesis processes in the liver, followed by improvement in glucose homeostasis and hepatic fat accumulation in aged rodents (AU)

• FAPESP's process: 18/07568-6 - The role of physical exercise on Rock protein pathway, and lipogenic regulation and gluconeogenesis in the liver of aged rats.
• Grantee: Vitor Rosetto Muñoz
• Support Opportunities: Scholarships in Brazil - Doctorate