Implications of mitonuclear imbalance and UPRmt in hypothalamic neurons in the genesis of Obesity

• Grant number: 19/21709-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2020
• End date: September 30, 2025
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Eduardo Rochete Ropelle
• Grantee: Eduardo Rochete Ropelle
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Associated researchers: Adelino Sanchez Ramos da Silva ; Johan Auwerx ; Dennys Esper Corrêa Cintra ; Fernando Moreira Simabuco ; José Rodrigo Pauli ; Leandro Pereira de Moura ; Licio Augusto Velloso ; Rodrigo Stellzer Gaspar
• Associated scholarship(s): 24/19374-2 - Technical improvement in molecular biology laboratory, BP.TT; 24/18283-3 - Effects of Liensinin on UPRmt markers and mitochondrial function in C2C12 cells., BP.IC; 23/04659-9 - Genomic sequencing of the arcuate nucleus of the hypothalamus of exercised mice., BP.MS; + associated scholarships 23/13285-5 - Technical improvement in molecular biology laboratory., BP.TT; 23/00328-8 - Technical Improvement in the Laboratory of Molecular Biology of Exercise, BP.TT; 22/00388-8 - Role of physical training on UPRmt in musculature skeleton of obese mice, BP.IC; 22/02350-8 - Effect of intermittent fasting on UPRmt in the hypothalamus of obese mice, BP.DD; 21/11812-2 - Evaluation of the effects of high fat diet and physical exercise on the expression of Parp1 and the protein parylation profile in the hypothalamic tissue, BP.IC; 21/04292-2 - Implications of interleukin-6 on UPRmt in the hypothalamus of obese mice, BP.PD - associated scholarships

Abstract

Excessive consumption of saturated fat alters the functionality of hypothalamic neurons that control energy homeostasis, directly contributing to the onset of the obese phenotype. Mitochondrial activity in subpopulations of hypothalamic neurons is closely related to the control of food intake and energy homeostasis. Consumption of high fat diets promotes deleterious signals that alter the morphological and functional characteristics of mitochondria in neurons. On the other hand, it is known that mitochondria have highly conserved mechanisms among species to reestablish proteostasis and mitochondrial function, among them the UPRmt, mitochondrial Unfolded Protein Response. UPRmt is activated by the loss of mitochondrial proteostasis generated by malformed proteins or by altering the balance between the production of proteins that form the mitochondrial complexes that are derived from both nuclear DNA (mDNA) and mitochondrial DNA (mtDNA). This mechanism is known as mitonuclear imbalance. However, the effects of saturated fat consumption on mitonuclear imbalance and mRPUU in hypothalamic neurons are still unknown. Bioinformatics analyzes will be combined with experiments in cell culture and experimental model of obesity in wild-type mice and genetically modified animals to evaluate the role of mitonuclear imbalance and hypothalamic UPRm in the control of energy homeostasis. In this context will also be evaluated two different therapeutic strategies, the use of nutrients and physical exercise. The development of the current project could provide new insights into the effects of high fat diet on the functioning of mitochondria in hypothalamic neurons, opening new perspectives for the treatment and prevention of obesity. (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)

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., 2022-10-13. (21/06291-3, 21/08693-1, 19/11820-5, 17/12765-2, 19/21709-4, 21/08692-5, 20/13443-1, 18/14818-9)

OLIVEIRA, LUCIANA DA COSTA; MORAIS, GUSTAVO PAROSCHI; DE OLIVEIRA, FRANCIANE PEREIRA; MATA, MILENE MONTAVONI; VERAS, ALLICE SANTOS CRUZ; DA ROCHA, ALISSON LUIZ; ELIAS, LUCILA LEICO KAGOHARA; TEIXEIRA, GIOVANA RAMPAZZO; DE MORAES, CAMILA; CINTRA, DENNYS E.; et al. Intermittent fasting combined with exercise training reduces body mass and alleviates hypothalamic disorders induced by high-fat diet intake. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 119, p. 12-pg., 2023-05-29. (16/17968-6, 20/08192-0, 19/17532-1, 17/25492-4, 19/21709-4, 21/06291-3)

CARNEIRO, FERNANDA S.; KATASHIMA, CARLOS K.; DODGE, JOSHUA D.; CINTRA, DENNYS E.; PAULI, JOSE RODRIGO; DA SILVA, ADELINO S. R.; ROPELLE, EDUARDO R.. Tissue-specific roles of mitochondrial unfolded protein response during obesity. Obesity Reviews, v. 25, n. 9, p. 15-pg., 2024-06-16. (22/02350-8, 21/04292-2, 19/21709-4)

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)

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, DEC 2021. (20/08192-0, 20/13443-1, 19/21709-4, 19/11820-5)

BRAGA, RENATA R.; CRISOL, BARBARA M.; BRICOLA, RAFAEL S.; SANT'ANA, MARCELLA R.; NAKANDAKARI, SUSANA C. B. R.; COSTA, SULEYMA O.; PRADA, PATRICIA O.; DA SILVA, ADELINO S. R.; MOURA, LEANDRO P.; PAULI, JOSE R.; et al. Exercise alters the mitochondrial proteostasis and induces the mitonuclear imbalance and UPRmt in the hypothalamus of mice. SCIENTIFIC REPORTS, v. 11, n. 1, FEB 15 2021. (17/18695-6, 13/07607-8, 18/07634-9, 19/21709-4)

GASPAR, RODRIGO STELLZER; KATASHIMA, CARLOS KIYOSHI; CRISOL, BARBARA MOREIRA; CARNEIRO, FERNANDA SILVA; SAMPAIO, IGOR; DOS REIS SILVEIRA, LEONARDO; DA SILVA, ADELINO SANCHEZ RAMOS; CINTRA, DENNYS ESPER; PAULI, JOSE RODRIGO; ROPELLE, EDUARDO ROCHETE. Physical exercise elicits UPRmt in the skeletal muscle: The role of c-Jun N-terminal kinase. MOLECULAR METABOLISM, v. 78, p. 11-pg., 2023-10-14. (15/06463-8, 19/21709-4, 20/13443-1, 19/11820-5)

BRICOLA, RAFAEL S.; CORDEIRO, ANDRE, V; CRISOL, BARBARA M.; BRAGA, RENATA R.; DE MELO, DIEGO G.; ROCHA, MATHEUS B.; GASPAR, RAFAEL C.; NAKANDAKARI, SUSANA C. B. R.; SILVA, VAGNER R. R.; ANARUMA, CHADI P.; et al. Aging reduces ABHD5 protein content in the adipose tissue of mice: The reversal effect of exercise. Cell Biochemistry and Function, v. N/A, p. 10-pg., 2022-12-14. (19/21709-4, 18/03122-3, 19/11820-5)

CRISOL, BARBARA M.; ROCHA, MATHEUS B.; FRANCO, BEATRIZ; MORELLI, ANA PAULA; KATASHIMA, CARLOS K.; JUNIOR, SCYLAS J. A.; CARNEIRO, FERNANDA S.; BRAGA, RENATA R.; DE AZAMBUJA, GRACIANA; COSTA, RAUL GOBATO; et al. Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment. MOLECULAR METABOLISM, v. 96, p. 15-pg., 2025-06-01. (18/04192-5, 19/21709-4, 22/08930-6, 21/08354-2, 19/22512-0, 13/07607-8)

KATASHIMA, CARLOS KIYOSHI; MICHELETTI, THAYANA DE OLIVEIRA; BRAGA, RENATA ROSSETO; GASPAR, RODRIGO STELLZER; GOEMINNE, LUDGER J. E.; MOURA-ASSIS, ALEXANDRE; CRISOL, BARBARA MOREIRA; BRICOLA, RAFAEL S.; SILVA, VAGNER RAMON R.; RAMOS, CAMILA DE OLIVEIRA; et al. Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism. SCIENCE ADVANCES, v. 8, n. 30, p. 14-pg., 2022-07-29. (12/23006-1, 19/21709-4, 13/26053-3, 18/04192-5)