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

Abstract

Notch1 protein has an important role in the hepatic metabolism. In fasting condition, Notch1 acts in the gluconeogenesis and in postprandial condition, it acts in the control of hepatic lipogenesis. In this way, it has been observed in obese individuals that Notch1 is correlated with insulin resistance in the liver and with non-fatty liver disease, which makes it an interesting research target. In the battle against metabolic disorders linked to excess body adiposity, the physical exercise has been used as a non-pharmacological intervention, since it is able to modulate proteins involved in both gluconeogenesis and lipogenesis. Such effects of exercise are associated with the prevention and treatment of hyperglycemia and fat accumulation in the liver. However, the mechanisms whereby physical exercise acts in the control of these pathways in the liver have not been fully elucidated. Thus, the present study aims to verify the role of physical exercise in the Notch1 protein modulation in the hepatic tissue of obese mice and its contribution in the control of lipogenesis and gluconeogenesis. For this, we will use obese mice induced by high fat diet and genetically modified animals (ob/ob). After the Obesity induction, obese mice will be divided into two groups: sedentary and trained. The trained animals group will perform treadmill-running protocol, with intensity corresponding to 70% of the maximum running speed, for a period of four weeks. At the end of the exercise protocol (24 hours later), hepatic tissue fragments will be extracted and analyzes of mRNA will be made through the RT-PCR technique, and the protein content of key molecules in the control of lipogenesis, gluconeogenesis and Notch1 signaling through the Western Blotting technique. We will also evaluate the fat accumulation in the hepatic tissue through the histology technique by oil red. We will verify the mitochondrial activity by the Oroboros equipment. Finally, we will use an inhibitor of Notch1 activity to confirm the effects of physical training on the modulation of hepatic Notch1 protein signaling. At the end of the experiment, it is expected to elucidate the main alterations in the main pathways involved in gluconeogenesis and lipogenesis, especially in the Notch1 pathway, in the different experimental groups, thus providing new mechanisms of physical exercise for metabolic disorders linked to Obesity and associated comorbidities. (AU)