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


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)

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Scientific publications (10)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MACEDO, ANA PAULA AZEVEDO; DA SILVA, ADELINO SANCHEZ RAMOS; PAULI, JOSE RODRIGO. The muscle clock: how does muscle physiology change in 24 h in response to exercise?. JOURNAL OF PHYSIOLOGY-LONDON, v. 600, n. 4, p. 2-pg., . (20/08192-0, 20/13443-1)
PINTO, ANA P.; MUNOZ, VITOR R.; DA ROCHA, ALISSON L.; ROVINA, RAFAEL L.; FERRARI, GUSTAVO D.; ALBERICI, LUCIANE C.; SIMABUCO, FERNANDO M.; TEIXEIRA, GIOVANA R.; PAULI, JOSE R.; DE MOURA, LEANDRO P.; et al. IL-6 deletion decreased REV-ERB alpha protein and influenced autophagy and mitochondrial markers in the skeletal muscle after acute exercise. FRONTIERS IN IMMUNOLOGY, v. 13, p. 13-pg., . (21/06291-3, 21/08693-1, 19/11820-5, 17/12765-2, 19/21709-4, 21/08692-5, 20/13443-1, 18/14818-9)
ANTUNES, GABRIEL CALHEIROS; DE LIMA, ROBSON DAMASCENO; LINS VIEIRA, RENAN FUDOLI; AZEVEDO MACEDO, ANA PAULA; MUNOZ, VITOR ROSETTO; ZAMBALDE, ERIKA PEREIRA; ROMEIRO, CAIO FELIPE; SIMABUCO, FERNANDO MOREIRA; PRADA, PATRICIA OLIVEIRA; RAMOS DA SILVA, ADELINO SANCHEZ; et al. Resistance exercise attenuates IKK epsilon phosphorylation and hepatic fat accumulation of obese mice. Clinical and Experimental Pharmacology and Physiology, v. 49, n. 10, p. 10-pg., . (20/13443-1)
MUNOZ, VITOR ROSETTO; BOTEZELLI, JOSE DIEGO; GASPAR, RAFAEL CALAIS; DA ROCHA, ALISSON L.; VIEIRA, RENAN FUDOLI LINS; CRISOL, BARBARA MOREIRA; BRAGA, RENATA ROSSETO; SEVERINO, MATHEUS BRANDEMARTE; NAKANDAKARI, SUSANA CASTELO BRANCO RAMOS; ANTUNES, GABRIEL CALHEIROS; et al. Effects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4(+/-) mice. CELLULAR AND MOLECULAR LIFE SCIENCES, v. 80, n. 5, p. 16-pg., . (16/18488-8, 21/08692-5, 15/26000-2, 19/11820-5, 20/13443-1, 18/20872-6)
AZEVEDO MACEDO, ANA PAULA; RAMOS DA SILVA, ADELINO SANCHEZ; MUNOZ, VITOR ROSETTO; ROPELLE, EDUARDO ROCHETE; PAULI, JOSE RODRIGO. Mitochondrial dysfunction plays an essential role in remodeling aging adipose tissue. MECHANISMS OF AGEING AND DEVELOPMENT, v. 200, . (20/08192-0, 20/13443-1, 19/21709-4, 19/11820-5)
MUNOZ, V. R.; GASPAR, R. C.; MANCINI, M. C. S.; DE LIMA, R. D.; VIEIRA, R. F. L.; CRISOL, B. M.; ANTUNES, G. C.; TROMBETA, J. C. S.; BONFANTE, I. L. P.; SIMABUCO, F. M.; et al. Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents. Journal of Endocrinological Investigation, v. N/A, p. 13-pg., . (16/18488-8, 19/11820-5, 18/20872-6, 21/08692-5, 20/13443-1, 15/26000-2)
MARAFON, BRUNO B.; PINTO, ANA P.; DE VICENTE, LARISSA G.; DA ROCHA, ALISSON L.; SIMABUCO, FERNANDO M.; ROPELLE, EDUARDO R.; DE MOURA, LEANDRO P.; CINTRA, DENNYS E.; PAULI, JOSE R.; DA SILVA, ADELINO S. R.. Genetic ablation of Toll-like Receptor 4 seems to activate the apoptosis pathway in the skeletal muscle of mice after acute physical exercise. Cell Biochemistry and Function, v. N/A, p. 12-pg., . (20/13443-1, 20/04269-8, 19/11820-5, 21/06291-3)
PINTO, ANA P.; MUNOZ, VITOR R.; TAVARES, MARIA EDUARDA A.; DOS SANTOS, JONATHAS R.; REBELO, MACARIO A.; ALBERICI, LUCIANE C.; SIMABUCO, FERNANDO M.; TEIXEIRA, GIOVANA R.; PAULI, JOSE R.; DE MOURA, LEANDRO P.; et al. Combined physical exercise reverses the reduced expression of Bmal1 in the liver of aged mice. Life Sciences, v. 312, p. 12-pg., . (21/08693-1, 21/08692-5, 20/13443-1, 21/06291-3, 19/11820-5)
GASPAR, RAFAEL C.; LYU, KUN; HUBBARD, BRANDON T.; LEITNER, BROOKS P.; LUUKKONEN, PANU K.; HIRABARA, SANDRO M.; SAKUMA, IKKI; NASIRI, ALI; ZHANG, DONGYAN; KAHN, MARIO; et al. Distinct subcellular localisation of intramyocellular lipids and reduced PKC epsilon/PKC theta activity preserve muscle insulin sensitivity in exercise-trained mice. Diabetologia, v. 66, n. 3, p. 12-pg., . (19/11338-9, 17/20542-3, 20/13443-1)

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