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Short-term aerobic physical exercise and hepatic metabolism: the role of ApoJ

Grant number: 19/04457-1
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): July 01, 2019
Effective date (End): June 30, 2020
Field of knowledge:Health Sciences - Physical Education
Principal Investigator:Leandro Pereira de Moura
Grantee:Rodrigo Martins Pereira
Supervisor abroad: Young-Bum Kim
Home Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
Local de pesquisa : Harvard University, Boston, United States  
Associated to the scholarship:16/12569-6 - Effects of different exercise intensities on clusterin metabolism and its interference on insulin signaling in rodents, BP.DD

Abstract

The World Health Organization estimated that in 2014 approximately 8.5% of the adult population had Type 2 diabetes (T2DM), a disease responsible for millions of deaths. Among the several mechanisms involved in the genesis of T2DM, failure of insulin action to inhibit hepatic glucose production (HGP) is one of the main factors contributing to hyperglycemia. In a healthy state, the insulin will initiate its cellular signaling in hepatocytes culminating in several effects, among which we can highlight: 1- the inhibition of gluconeogenesis and 2- induction of hepatic lipogenesis, through activation of SREBP-1c protein. However, in the condition of T2DM, insulin fails to inhibit the gluconeogenesis, but the lipogenic stimulus mediated by SREBP-1c remains active. This phenomenon is known as selective insulin resistance, and its mechanisms are not still understood. In this context, a new protein called clusterin or apolipoprotein J (Apo-J) has been gaining attention. Apo-J knockout obese mice present more severe insulin resistance compared to their wild type controls, even without changes in body composition. Similarly, hepatocytes of animals with Apo-J deletion showed a reduction in Akt phosphorylation after insulin stimulus. In the same way, a series of studies with different cell lines revealed a close relationship between Apo-J and the activation of proteins of the canonical insulin pathway, which allowed us to believe that Apo-J may be a protein of great importance in the control of hepatic metabolic functions. However, Apo-J could play a regulatory role on SREBP-1c activity in response to insulin, reducing the content of proteins involved with lipogenesis as FAS, ACC and SCD. Thus, in a condition of nutrient abundance, SREBP-1c has its activity increased, inducing both Apo-J and lipogenic genes expression. However, by a negative feedback mechanism, Apo-J inhibits the SREBP-1c expression. Thus, it is of great importance to identify new strategies that increase hepatic insulin sensitivity. There are several numbers of evidence the paradoxical role of aerobic exercise on the insulin action in the liver, increasing the Akt phosphorylation after insulin stimulus and reducing the HGP, but also reducing the synthesis of lipids, reverting the selective insulin resistance. However, Apo-J participation in selective insulin resistance and the effect of aerobic exercise in this scenario are not yet established. In this sense, we believe that Apo-J may be a new protein involved in this fine control of the metabolic functions of the liver, with great relevance to new strategies to combat the loss of control of HPG and NAFLD associated to obesity and T2DM. Therefore, the objective of the present project is to investigate the involvement of hepatic Apo-J on gluconeogenesis and fat liver accumulation and the effect of aerobic exercise in this scenario, submitting liver-specific Apo-J knockout obese mice to short-term aerobic physical exercise. Finally, we will also investigate whether the effects of short-term aerobic physical exercise on hepatic metabolism are mediated by hepatic Apo-J without interference of adipose tissue amount. It is important to note that although many studies show that aerobic exercise is able to provide better control of HGP and reduction of NAFLD, these results are accompanied by reduction of body fat, questioning if they are direct effects provided by the exercise or if they are secondary effects provided by reduction of adiposity. Thus, the short-term aerobic physical exercise protocol was chosen for our study (5 days of exercise), since previous studies of our laboratory showed that this is an exercise model that does not provide reduction of the adiposity of the animals.