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

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
(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; DE MOURA, LEANDRO PEREIRA; ROPELLE, EDUARDO ROCHETE; ZAGHLOUL, IMAN; MEKARY, RANIA A.; PAULI, JOSE RODRIGO. 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, JAN 2021. Web of Science Citations: 0.

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