The role of physical exercise on molecular pathways of glucose uptake in GLUT-4 knockout mice

• Grant number: 16/18488-8
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2017
• End date: February 28, 2019
• 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

It is known that chronic hyperglycemia over the years is associated with several systemic changes in the body and the malfunction of this regulation may lead to the appearance of a large spectrum of disorders in metabolism that grouped are called cardiometabolic syndrome. Thus, it is important to unfold the mechanisms by which glucose homeostasis is regulated and, what the main molecules involved in this control. A well-known agent that generates substantially significant responses in the regulation of glucose uptake is the physical exercise. This energy imbalance triggers the activation of many mechanisms increasing glucose transport blood to the intracellular environment through the glucose transporters. However, these adjustments have not yet been fully described in the literature. For this, the main purpose of this study is to compare the impact of different exercise protocols in glucose uptake independent (exercise control) and insulin dependent (molecular control) pathways. We will use control mice (GLUT+/+) and genetically engineered GLUT4+/- 120 days old. These animals will be distributed into four distinct groups (GLUT4+ /+ Sedentary, GLUT4+/- Sedentary, GLUT4+/- Endurance, GLUT4+/- Strength). During and in the end of the experiment, we will analyze some the adaptations resulted from exercise: glucose tolerance , insulin sensitivity , biochemical parameters ( glucose , cholesterol , and triglycerides , proteins involved in the synthesis of GLUT4 ( MEF and GEF ), glucose uptake regulated by muscle contraction and energy imbalance (AMPK, pAMPK, CaMKII, pCaMKII, AS160) and by insulin action on in the muscle (IR/pIR; IRS-1/pIRS-1; PI3K/pPI3K, IRS-1/PI3K, Akt/pAkt, AS160, GLUT4) and finally the presence of GLUT4 in the membrane. In the adipose tissue, we will analyze the IR/IRS-1, Akt, AS160, PPAR-³, PRDM16 e Glut-4 proteins. This analyzes will be performed using molecular biology techniques such as western blotting, immunofluorescence and qPCR. At the end of the experiment, we expect to elucidate the differences between these two major kinds of exercise in the synthesis and translocation of GLUT4, thereby providing new therapeutic possibilities and treatment for disorders evolving the cardiometabolic syndrome. (AU)

Scientific publications

(16)

(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)

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, VITOR ROSETTO; GASPAR, RAFAEL CALAIS; KUGA, GABRIEL KEINE; BETIM PAVAN, ISADORA CAROLINA; SIMABUCO, FERNANDO MOREIRA; RAMOS DA SILVA, ADELINO SANCHEZ; DE MOURA, LEANDRO PEREIRA; CINTRA, DENNYS ESPER; ROPELLE, EDUARDO ROCHETE; PAULI, JOSE RODRIGO. The Effects of Aging on Rho-Kinase and Insulin Signaling in Skeletal Muscle and White Adipose Tissue of Rats. JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, v. 75, n. 3, p. 432-436, MAR 2020. (12/13558-7, 16/18488-8, 15/26000-2)

GASPAR, RAFAEL CALAIS; MUNOZ, VITOR ROSETTO; KUGA, GABRIEL KEINE; BRANCO RAMOS NAKANDAKARI, SUSANA CASTELO; CRISOL, BARBARA MOREIRA; LENHARE, LUCIEN; BREDA, LEONARDO; BOTEZELLI, JOSE DIEGO; SANT'ANA, MARCELLA RAMOS; DA SILVA, ADELINO S. R.; et al. Acute physical exercise increases APPL1/PI3K signaling in the hypothalamus of lean mice. European Journal of Neuroscience, v. 50, n. 7, JULY 2019. (16/18488-8)

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)

GASPAR, RAFAEL CALAIS; MUNOZ, VITOR ROSETTO; KUGA, GABRIEL KEINE; BRANCO RAMOS NAKANDAKARI, SUSANA CASTELO; MINUZZI, LUCIELE GUERRA; BOTEZELLI, JOSE DIEGO; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; ROPELLE, EDUARDO ROCHETE; et al. Acute physical exercise increases leptin-induced hypothalamic extracellular signal-regulated kinase1/2 phosphorylation and thermogenesis of obese mice. Journal of Cellular Biochemistry, v. 120, n. 1, p. 697-704, JAN 2019. (16/18488-8)

MUNOZ, VITOR ROSETTO; GASPAR, RAFAEL CALAIS; CRISOL, BARBARA MOREIRA; FORMIGARI, GUILHERME PEDRON; SANT'ANA, MARCELLA RAMOS; BOTEZELLI, JOSE DIEGO; GASPAR, RODRIGO STELLZER; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; et al. Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice. Journal of Physiological Sciences, v. 68, n. 4, p. 493-501, JUL 2018. (13/21491-2, 16/18488-8)

GASPAR, RAFAEL CALAIS; MUNOZ, VITOR ROSETTO; FORMIGARI, GUILHERME PEDRON; KUGA, GABRIEL KEINE; BRANCO RAMOS NAKANDAKARI, SUSANA CASTELO; BOTEZELLI, JOSE DIEGO; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; ROPELLE, EDUARDO ROCHETE; et al. Acute physical exercise increases the adaptor protein APPL1 in the hypothalamus of obese mice. CYTOKINE, v. 110, p. 87-93, OCT 2018. (16/18488-8)

MINUZZI, LUCIELE GUERRA; KUGA, GABRIEL KEINE; BREDA, LEONARDO; GASPAR, RAFAEL CALAIS; MUNOZ, VITOR ROSETTO; PEREIRA, RODRIGO MARTINS; BOTEZELLI, JOSE DIEGO; DA SILVA, ADELINO S. R.; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; et al. Short-term Resistance Training Increases APPL1 Content in the Liver and the Insulin Sensitivity of Mice Fed a Long-term High-fat Diet. EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES, v. 128, n. 1, p. 30-37, JAN 2020. (16/18488-8)

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)

MUNOZ, VITOR R.; GASPAR, RAFAEL C.; SEVERINO, MATHEUS B.; MACEDO, ANA P. A.; SIMABUCO, FERNANDO M.; ROPELLE, EDUARDO R.; CINTRA, DENNYS E.; DA SILVA, ADELINO S. R.; KIM, YOUNG-BUM; PAULI, JOSE RODRIGO. Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice. FRONTIERS IN IMMUNOLOGY, v. 12, JUN 21 2021. (16/18488-8, 13/21491-2, 15/26000-2)

CANCIGLIERI, PAULO HENRIQUE; KUGA, GABRIEL KEINE; MUNOZ, VITOR ROSETTO; GASPAR, RAFAEL CALAIS; DA ROCHA, ALISSON LUIZ; BREDA, LEONARDO; ANARUMA, CHADI PELLEGRINI; MINUZZI, LUCIELE GUERRA; RAMOS DA SILVA, ADELINO SANCHEZ; CINTRA, DENNYS ESPER; et al. The reversal effect of physical exercise on aging-related increases in APPL2 content in skeletal muscle. Life Sciences, v. 210, p. 209-213, OCT 1 2018. (16/18488-8)

BRANCO RAMOS NAKANDAKARI, SUSANA CASTELO; MUNOZ, VITOR ROSETTO; KUGA, GABRIEL KEINE; GASPAR, RAFAEL CALAIS; SANT'ANA, MARCELLA RAMOS; BETIM PAVAN, ISADORA CAROLINA; SALVINO DA SILVA, LUIZ GUILHERME; MORELLI, ANA PAULA; SIMABUCO, FERNANDO MOREIRA; RAMOS DA SILVA, ADELINO SANCHEZ; et al. Short-term high-fat diet modulates several inflammatory, ER stress, and apoptosis markers in the hippocampus of young mice. BRAIN BEHAVIOR AND IMMUNITY, v. 79, p. 284-293, JUL 2019. (16/18488-8)

GASPAR, RAFAEL CALAIS; BOTEZELLI, JOSE DIEGO; KUGA, GABRIEL KEINE; MUNOZ, VITOR ROSETTO; COOPE, ANDRESSA; PEREIRA, RODRIGO MARTINS; RAMOS DA SILVA, ADELINO SANCHEZ; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; ROPELLE, EDUARDO ROCHETE; et al. High Dosage of Vitamin D Regulates the Energy Metabolism and Increases Insulin Sensitivity, but are Associated with High Levels of Kidney Damage. Drug Development Research, v. 78, n. 5, p. 203-209, AUG 2017. (16/18488-8, 13/20293-2)

RODRIGUES, BARBARA DE A.; MUNOZ, VITOR R.; KUGA, GABRIEL K.; GASPAR, RAFAEL C.; NAKANDAKARI, SUSANA C. B. R.; CRISOL, BARBARA M.; BOTEZELLI, JOSE D.; PAULI, LUCIANA S. S.; DA SILVA, ADELINO S. R.; DE MOURA, LEANDRO P.; et al. Obesity Increases Mitogen-Activated Protein Kinase Phosphatase-3 Levels in the Hypothalamus of Mice. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 11, OCT 9 2017. (13/21491-2, 16/18488-8, 13/25512-4)

RODRIGUES, BARBARA DE ALMEIDA; KUGA, GABRIEL KEINE; MUNOZ, VITOR ROSETTO; GASPAR, RAFAEL CALAIS; TAVARES, MARIANA ROSOLEN; BOTEZELLI, JOSE DIEGO; RAMOS DA SILVA, ADELINO SANCHEZ; CINTRA, DENNYS ESPER; DE MOURA, LEANDRO PEREIRA; SIMABUCO, FERNANDO MOREIRA; et al. Overexpression of Mitogen-activated protein kinase phosphatase-3 (MKP-3)reduces FoxO1 phosphorylation in mice hypothalamus. Neuroscience Letters, v. 659, p. 14-17, OCT 17 2017. (16/18488-8, 13/25512-4)

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)