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Neuronal autophagy modulation in response to fatty acids in vitro and in vivo: relationship with inflammatory pathways

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Author(s):
Andressa Reginato
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas
Defense date:
Examining board members:
Marciane Milanski; Augusto Ducati Luchessi; Fernando Moreira Simabuco; Karina Thieme; Marcia Queiroz Latorraca
Advisor: Adriana Souza Torsoni; Marciane Milanski
Abstract

Autophagy is a lysosomal degradation pathway that helps cells to sustain viability by degrading, for example, senescent organelles and protein aggregates. Alterations in autophagy activity in the hypothalamus tissue seems to disrupt energy balance control as well as impairing neuronal activity. In this work, our objective was to investigate the relationship between lipids and neuronal autophagy modulation. Therefore, we initially used an acute exposure model by feeding animals with high fat diet (HFD) for 1 and 3 days. Under these conditions we found that the diet is capable of altering metabolic and inflammatory parameters of mice, associated with alterations in gene expression of autophagy markers in hypothalamic tissue. Nevertheless, the global autophagy activity seems to be preserved, since it was not possible to observe statistical difference in the protein content of important process markers. We also evaluated the effect of palmitate (PA) intracerebroventricular (i.c.v) treatment, an important saturated fatty acid. Again, we found only alterations in gene expression of autophagy markers. Finally, using culture of immortalized hypothalamic neurons expressing Npy / AgRP, we found that palmitate was characterized as an important inducer of autophagy activity, associated with disturbances in cell viability. Interestingly, there was no induction in the autophagic process when we used a mixture containing saturated and unsaturated fatty acids. In addition, palmitoleic (PO) fatty acid, an important unsaturated fatty acid that has the same number of carbons as PA, was able to decrease autophagy activity in neurons. When we performed a co-treatment between PA combined with PO, we found that the PA-induced autophagy was attenuated. The same effect was found when we pretreated the neurons with the drug miriocin, an important inhibitor of de novo ceramide synthesis. We also evaluated the influence of the TLR4 pathway on induction of autophagy in response to PA by blocking the receptor with the comercial drug TAK242. We found that under these conditions, PA remained inducing autophagy. Thus, we conclude in this project that the saturation of lipids chain seems to be responsible for different neuronal autophagy modulation profiles with and ceramide synthesis being an important promising target. The establishment of the relationship between dietary lipids and autophagy modulation in neurons that control food intake may represent an important step in identifying therapeutic targets for obesity control, an important public health problem in our society (AU)

FAPESP's process: 15/25710-6 - Hypothalamic autophagy evaluation in response to treatment with saturated fatty acid in vitro and in vivo: connections with inflammatory pathways
Grantee:Andressa Reginato
Support type: Scholarships in Brazil - Doctorate