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Role of kallikrein kinin system on metabolism and repercussion on voluntary exercise


Physical inactivity is one of the causes of the epidemic of obesity and diabetes. The World Health Organization showed in 2018 that around 28% of the world population had insufficient physical activity and Latin America has one of the highest rates of inactivity. Thus, it is important to evaluate the molecular mechanisms involved in the practice of physical exercise, the mediators involved in spontaneous physical activity, as well as the impact of physical exercise on metabolism and the immune system. Kinins, are the final mediators of the kallikrein-kinin system (KKS), participating in inflammatory processes, mediating pain and controlling blood pressure. Recent results from our group showed the involvement of this system in the modulation of physical exercise, metabolism and obesity. Invariant Natural Killer (iNKT) plays an important role on immune system and metabolism, however, the role of this molecule in the exercise + metabolism is missing. Ppar alpha is an important transcripiton factor related to lipid metabolism and the Ppar alpha KO can help us to understand the role of lipid metabolism in voluntary wheel running. Thus, the objective of this project is to evaluate the role of the kallikrein kinins system, iNKT and Ppar alpha in voluntary exercise. In order to assess whether kinin receptors influence metabolism, B1 KO will be placed in boxes with voluntary wheels and submitted to fed and fasted states for 48 hours. To address the importance of lipid metabolism in the liver, as well as that of ketone bodies to voluntary activity, animals Ppar alpha KO will be submitted to the same protocols (subproject 1). In humans, a group of type 2 diabetics will be investigated and the polymorphism of the kinin B2 receptor promoter, which is related to its expression, will be the target of research (subproject 2). The role of the kinin B1 receptor in the placenta and pregnancy, modulating the metabolism of offspring, through transgenerational pathways will be evaluated (subproject 3) We intend, in subproject 4, to evaluate the response of iNKT cells in metabolism and ketogenesis through nutritional modifications and/or physical exercise practices. We will also verify the central role of the kinin B2 receptor in water control and food search through the generation of conditional deficient animals for the B2 receptor in the hypothalamic nuclei (subproject 5). The influence of physical activity of genitors modulating the children's renal inflammatory responses will be investigated by nephrotoxic drug administration (subproject 6). (AU)

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