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Role of physical exercise in the regulation of Notch1 protein in obese mice : effects on hepatic lipogenesis and gluconeogenesis

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Rafael Calais Gaspar
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas
Defense date:
Examining board members:
Igor Luchini Baptista; Ellen Cristini de Freitas; Carlos Kiyoshi Katashima; Maíra Felonato
Advisor: José Rodrigo Pauli

The Notch1 protein plays an important role in liver metabolism, acting in the control of glucose production and lipid metabolism, directly impacting liver damage caused by obesity, making it an important research target. On the other hand, the physical exercise has been suggested as a highly effective non-pharmacological intervention in the control of obesity disorders, however, the mechanisms linked to it have not been fully unveiled. Therefore, this study aims to verify the effects of physical exercise on the modulation of Notch1 protein in the liver tissue of obese mice and its contribution to the control of lipogenesis and gluconeogenesis. Thus, it was found that obese animals, diet-induced, were resistant to insulin and showed increased Notch1 protein content and activation, but physical exercise was able to improve the glycemic homeostasis, to reduce hepatic Notch1 activation, especially the expression of Presinilin-1, which is important in the activation of Notch1. Furthermore, it was observed a reduction in the protein content of the regulatory proteins of gluconeogenesis and hepatic lipogenesis in trained animals besides increased mitochondrial respiration, compared to sedentary group. Such findings were confirmed through inhibition of the ?-secretase complex, where an attenuation of tolerance to pyruvate was observed, as well as a reduction in Notch1 signaling in the liver of obese animals. Nevertheless, it was noted that obese B6.V-Lepob/JUnib (ob/ob) mice showed a significant increase in Notch1 activation and aerobic training was able to reduce the cleaved domain of Nocth1 as well as key proteins controlled by it. Finally, it was found that the overexpression of Notch1 and NICD in liver cells resulted in an increase in gluconeogenesis and lipogenesis enzymes, corroborating the in vivo results. Therefore, the results found in the study elucidate, for the first time, new mechanisms by which physical exercise acts to improve liver metabolism and suggests Notch1 as a potential therapeutic target in the damage associated with obesity (AU)

FAPESP's process: 17/20542-3 - Role of physical exercise in regulation of Notch1 protein in obese mice: effects on hepatic lipogenesis and gluconeogenesis
Grantee:Rafael Calais Gaspar
Support type: Scholarships in Brazil - Doctorate