Effects of physical exercise on Rock protein signaling pathway, and lipogenic regulation and gluconeogenesis in the liver of aged rats

• Grant number: 18/20872-6
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2019
• End date: February 28, 2021
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: José Rodrigo Pauli
• Grantee: José Rodrigo Pauli
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Associated researchers: Adelino Sanchez Ramos da Silva

Abstract

During the process of senescence, some factors such as the physiological function declining, the increased high fat food intake, and the inactivity are related with impairments in the hepatic metabolism leading to hepatic fat accumulation, also known as nonalcoholic fatty liver disease (NAFLD). Once the NAFLD is presented, there is a risk for non-alcoholic steatohepatitis (NASH) development leading to even more severe impairments in quality of life and life expectancy. In this context, we have sought to identify molecules with regulatory role in the insulin-signaling pathway, so in the lipogenesis and gluconeogenesis processes in the hepatic tissue, and the physical exercise participation in aged organisms. In this context, studies have showed the role of Rho-kinase (Rock) protein to mediate the insulin pathway through the insulin recepetor substrate 1 (IRS-1) phosphorylation at serine 632/635 residue, and thereby increasing the glucose uptake in the skeletal muscle. However, recent studies have also shown that Rock may have a negative effect in the liver, being involved with lipogenesis and hepatic glucose production. Thus, the aim of this study will be to evaluate the effects of physical exercise on Rock signaling pathway, and the effects on lipogenesis and gluconeogenesis in the lliver of old rats. Wistar and Fischer 344 rats will be used and separated in Young (3-5 months old) and Old (17 months old), also in sedentary and trained. The physical exercise training protocol will be the swimming exercise, with 120 minutes of duration, 5 times/week, during 7 days. At the end of the experiment, the adaptions resulting from physical exercise will be evaluated, such as: glucose tolerance, insulin sensitivity, pyruvate tolerance, glycaemia, insulinemia and hepatic glycogen. At the molecular level, will be measured the Rock1 and Rock2 protein, the Rock activator (RhoA) and inhibitory (RhoE), the IRS-1 serine 632/635 and tyrosine 612 phosphorylation, pAkt and total Akt, pGSK3 and total GSK3, and other proteins related to lipogenesis and hepatic glucose production in the liver. For the molecular analysis will be performed immunoblotting and Real time PCR. Moreover, to elucidate the specific mechanism through Rock can be modulated, we will inhibit (Y-27632) and overexpress this protein in HepG2 cells. In summary, it is expected to elucidate the aerobic physical exercise effects on Rock metabolism and the repercussions on lipogenesis and gluconeogenesis in the liver of old rats. (AU)

Scientific publications

(11)

(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)

VIEIRA, RENAN FUDOLI LINS; MUNOZ, VITOR ROSETTO; JUNQUEIRA, RAFAEL LIMA; DE OLIVEIRA, FELLIPE; GASPAR, RAFAEL CALAIS; NAKANDAKARI, SUSANA CASTELO BRANCO RAMOS; COSTA, SULEYMA DE OLIVEIRA; TORSONI, MARCIO ALBERTO; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; et al. ime-restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high-fat die. JOURNAL OF PHYSIOLOGY-LONDON, v. 600, n. 4, SI, JAN 2021. (19/00227-1, 19/21709-4, 18/20872-6)

GASPAR, RAFAEL CALAIS; MUNOZ, VITOR ROSETTO; BRANCO RAMOS NAKANDAKARI, SUSANA CASTELO; LINS VIEIRA, RENAN FUDOLI; DA CONCEICAO, LUCIANA RENATA; DE OLIVEIRA, FELLIPE; CRISOL, BARBARA MOREIRA; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; et al. Aging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats. Experimental Gerontology, v. 139, OCT 1 2020. (19/00227-1, 18/20872-6, 17/20542-3, 18/07568-6)

GASPAR, RAFAEL C.; NAKANDAKARI, SUSANA C. B. R.; MUNOZ, VITOR R.; VIEIRA, RENAN F. L.; DA SILVA, ADELINO S. R.; CINTRA, DENNYS E.; DE MOURA, LEANDRO P.; ROPELLE, EDUARDO R.; PAULI, JOSE RODRIGO. Acute physical exercise increases PI3K-p110 alpha protein content in the hypothalamus of obese mice. Journal of Anatomy, v. 238, n. 3, p. 743-750, MAR 2021. (17/20542-3, 18/07568-6, 18/20872-6)

MUNOZ, VITOR ROSETTO; GASPAR, RAFAEL CALAIS; MINUZZI, LUCIELE GUERRA; CANCIGLIERI, RAPHAEL DOS SANTOS; RAMOS DA SILVA, ADELINO SANCHEZ; DE MOURA, LEANDRO PEREIRA; CINTRA, DENNYS ESPER; ROPELLE, EDUARDO ROCHETE; PAULI, JOSE RODRIGO. Rho-kinase activity is upregulated in the skeletal muscle of aged exercised rats. Experimental Gerontology, v. 128, DEC 2019. (18/20872-6, 15/26000-2, 16/18488-8)

GASPAR, RAFAEL C.; PAULI, JOSE R.; SHULMAN, I, GERALD; MUNOZ, VITOR R.. An update on brown adipose tissue biology: a discussion of recent findings. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 320, n. 3, p. E488-E495, MAR 2021. (19/00227-1, 19/11338-9, 18/07568-6, 18/20872-6)

MINUZZI, LUCIELE GUERRA; DA CONCEICAO, LUCIANA RENATA; MUNOZ, VITOR ROSETTO; VIEIRA, RENAN FUDOLI LINS; GASPAR, RAFAEL CALAIS; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; ROPELLE, EDUARDO ROCHETE; TEIXEIRA, ANA MARIA; et al. Effects of short-term physical training on the interleukin-15 signalling pathway and glucose tolerance in aged rats. CYTOKINE, v. 137, JAN 2021. (18/20872-6)

ROPELLE, EDUARDO ROCHETE; RAMOS DA SILVA, ADELINO SANCHEZ; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; TEIXEIRA, ANA MARIA; PAULI, JOSE RODRIGO. Physical Exercise: A Versatile Anti-Inflammatory Tool Involved in the Control of Hypothalamic Satiety Signaling. EXERCISE IMMUNOLOGY REVIEW, v. 27, p. 17-pg., 2021-01-01. (19/00227-1, 18/20872-6, 18/07634-9)

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., 2023-05-01. (16/18488-8, 21/08692-5, 15/26000-2, 19/11820-5, 20/13443-1, 18/20872-6)

MUNOZ, VITOR ROSETTO; GASPAR, RAFAEL CALAIS; ESTECA, MARCOS VINICIUS; BAPTISTA, IGOR LUCHINI; LINS VIEIRA, RENAN FUDOLI; RAMOS DA SILVA, ADELINO SANCHEZ; DE MOURA, LEANDRO PEREIRA; CINTRA, DENNYS ESPER; ROPELLE, EDUARDO ROCHETE; PAULI, JOSE RODRIGO. Physical exercise increases ROCK activity in the skeletal muscle of middle-aged rats. MECHANISMS OF AGEING AND DEVELOPMENT, v. 186, MAR 2020. (16/18488-8, 15/26000-2, 18/20872-6)

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., 2022-11-01. (16/18488-8, 19/11820-5, 18/20872-6, 21/08692-5, 20/13443-1, 15/26000-2)

VIEIRA, RENAN FUDOLI LINS; MUNOZ, VITOR ROSETTO; JUNQUEIRA, RAFAEL LIMA; DE OLIVEIRA, FELLIPE; GASPAR, RAFAEL CALAIS; NAKANDAKARI, SUSANA CASTELO BRANCO RAMOS; COSTA, SULEYMA DE OLIVEIRA; TORSONI, MARCIO ALBERTO; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; et al. Time-restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high-fat diet. JOURNAL OF PHYSIOLOGY-LONDON, v. 600, n. 4, p. 17-pg., 2021-01-26. (19/00227-1, 18/20872-6, 19/21709-4)