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Effects of the combination of intermittent fasting with physical exercise on the hypothalamic autophagy pathway in obese mice

Grant number: 17/25492-4
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2018
Effective date (End): September 30, 2022
Field of knowledge:Health Sciences - Nutrition
Principal Investigator:Adelino Sanchez Ramos da Silva
Grantee:Luciana da Costa Oliveira
Host Institution: Escola de Educação Física e Esporte de Ribeirão Preto (EEFERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


The medial basal hypothalamus is composed of AgRP orexigenic neurons and POMC anorectic neurons, which are involved in the regulation of food intake and energy expenditure. It is known that obese individuals present impaired hypothalamic neuronal caused by the increased expression of inflammatory proteins in this region leading to impairment in leptin and insulin signaling. Thus, the expected anorectic effects induced by the hormones through modulations in the autophagic pathway are impaired, establishing a chronic condition of hyperphagic behavior, higher feeding efficiency (ratio of weight change/food intake) and increased body adiposity. Intermittent Fasting (IF), a popular diet, is able to modulate the expression of neuropeptides, reduce body fat even without the reduction of caloric intake, and increase daily energy expenditure in obese individuals, thereby suggesting the existence of modulations in the leptin pathway and autophagy in the hypothalamus. However, these responses have not yet been investigated. In addition, Physical Exercise (PE) is able to induce an anti-inflammatory effect in the hypothalamus reestablishing the leptin pathway. Thus, it is possible to hypothesize that the combination of IF and PE will have better effects on the reestablishment of hypothalamic autophagic control in obese individuals. This research project aims to investigate the effect of the association of IF with PE in the inflammatory, leptin and autophagy pathways in the hypothalamus of obese mice. The mice will be divided into 5 groups: Thin Control (C); Obese Control (O); Intermittent Fasting (IF); Trained (TR) and Trained Intermittent Fasting (TRF). Before and after the training protocols and/or IF (24 hours) will be evaluated the metabolic variables: caloric expenditure (by indirect calorimetry), body composition (by DEXA), insulin sensitivity (by insulin tolerance test) and serum levels of insulin and leptin. Body weight and food intake will be evaluated weekly. After the euthanasia, 4 different techniques will be performed: a) Immunoblotting: for analysis of the hypothalamic inflammatory pathway and central response to leptin; b) Real-Time PCR: for analysis of the expression of anorexigenic neuropeptides (POMC and CART) and orexigenic (NPY and AgRP); c) Immunofluorescence: to analyze the behavior of the autophagic pathway in the medial basal hypothalamus. According to the statistical distribution of the data, parametric or non-parametric tests will be used, and level of significance pd0.05. (AU)

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Scientific publications
(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)
OLIVEIRA, LUCIANA DA COSTA; MORAIS, GUSTAVO PAROSCHI; ROPELLE, EDUARDO R.; DE MOURA, LEANDRO P.; CINTRA, DENNYS E.; PAULI, JOSE R.; DE FREITAS, ELLEN C.; RORATO, RODRIGO; DA SILVA, ADELINO SANCHEZ R.. Using Intermittent Fasting as a Non-pharmacological Strategy to Alleviate Obesity-Induced Hypothalamic Molecular Pathway Disruption. FRONTIERS IN NUTRITION, v. 9, p. 15-pg., . (17/25492-4, 20/08192-0)
DA ROCHA, ALISSON L.; PINTO, ANA P.; BEDO, BRUNO L. S.; MORAIS, GUSTAVO P.; OLIVEIRA, LUCIANA C.; CAROLINO, RUITHER O. G.; PAULI, JOSE R.; SIMABUCO, FERNANDO M.; DE MOURA, LEANDRO P.; ROPELLE, EDUARDO R.; et al. Exercise alters the circadian rhythm of REV-ERB-alpha and downregulates autophagy-related genes in peripheral and central tissues. SCIENTIFIC REPORTS, v. 12, n. 1, p. 13-pg., . (21/08693-1, 19/17532-1, 17/25492-4, 19/11820-5, 17/19869-8, 17/12765-2)
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., . (16/17968-6, 20/08192-0, 19/17532-1, 17/25492-4, 19/21709-4, 21/06291-3)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
OLIVEIRA, Luciana da Costa. Effects of the combination of intermittent fasting and physical exercise on autophagic and leptin pathway in the hypothalamus of obese mice. 2022. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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