Implications of aerobic exercise on the Notch 1 signaling pathway and regulation of lipogenesis and gluconeogenesis in the liver

Abstract

Obesity and diabetes are two major serious public health problems worldwide, with significant economic and social impact and consequent burden of morbidity and mortality in the population. The main risk factors for the development of obesity and diabetes are physical inactivity and unbalanced nutrition. Advanced age and family history complete this list of the most significant risk factors linked to the etiology of these diseases. Insulin resistance is a condition that precedes the development of type 2 diabetes mellitus (type 2 DM) and is related to the increase in lipid content and exacerbated glucose production in the liver. Such metabolic disturbances in fat and carbohydrate metabolism in the liver correlate with hyperglycemia and non-alcoholic fatty liver disease (NAFLD). However, the intracellular mechanisms involved in regulating the processes of lipogenesis and gluconeogenesis in liver tissue have not yet been fully understood. It has been shown that the Notch1 pathway can play a relevant role in the process of glucose production in the fasting state and increase in liver lipid content after meals. From this perspective, Notch1 signaling becomes a promising way of combating metabolic disorders linked to insulin resistance and type 2 DM. Therefore, they need to identify which Notch1 activators or inhibitors with potential preventive and treatment of the fat accumulation and exacerbated gluconeogenesis in the liver. Physical exercise is a strategy that when performed regularly can provide health benefits and liver metabolism. However, it is necessary to investigate whether physical exercise is able to regulate the Notch1 signaling pathway and contribute to the control of lipogenesis and gluconeogenesis in the liver. Therefore, this research proposal has as main objective to investigate the role of physical exercise in the regulation of Notch1 protein and its effects on lipogenesis and gluconeogenesis in the liver of rodents. For that, cell tests will be carried out and different models of mice will be used to assess the impact of obesity and hyperglycemia on the Notch1 signaling pathway in the liver and the effect of physical exercise. The present study will have three stages during its development. The first stage seeks to characterize the hypotheses in cell cultures of hepatocytes from humans and mice. After analysis in cell cultures, different models of mice will be used, including Swiss rodents, ob/ob, and TLR4 KO in order to verify the physiological and molecular changes in these rodents linked to the Notch1 signaling pathway. Finally, the last stage of the project aims to elucidate the effects of aerobic physical training under the Notch1 signaling pathway and its impact on glycemic homeostasis and lipid metabolism in the animals' liver. At the end of the experiment, it is expected to elucidate which are the main changes in the pathways involved in gluconeogenesis and lipogenesis, especially the Notch1 signaling pathway, in the different experimental groups, thus providing new mechanisms of action of physical exercise for the metabolic disorders linked obesity and type 2 DM. (AU)