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| Author(s): |
Mariana Portovedo
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Limeira, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas |
| Defense date: | 2018-01-18 |
| Examining board members: |
Marciane Milanski;
Licio Augusto Velloso;
Hosana Gomes Rodrigues;
Rodrigo Ferreira de Moura;
Maria Esméria Corezola do Amaral
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| Advisor: | Adriana Souza Torsoni; Marciane Milanski |
| Abstract | |
Obesity has become a global health issue and is directly related to increased risk of developing other metabolic diseases. A healthy lifestyle, including a balanced diet, is essential for the maintenance of a healthy body mass. Mammals have a powerful system responsible for the regulation of energy homeostasis. Neurons from hypothalamus are responsible for the coupling between food intake and satiety. These neurons are affected by lipid excess, especially long-chain saturated fatty acids and obesity. A subclinical inflammatory state is the hallmark of obesity. Also, obesity leads to the dysregulation of several systems related to stress response. In mice with diet-induced obesity, there is a failure in the regulation of macroautophagy and ubiquitin-proteasome system in hypothalamic neurons. These systems are responsible for the cytosolic protein renewal and therefore for cellular proteostasis. This work aimed to study the chaperone-mediated autophagy modulation in obese mice. This type of autophagy is responsible for the degradation of proteins which have a specific amino acid motif. There are two main proteins responsible for chaperone-mediated autophagy machinery, called HSC-70 and LAMP-A. Our results showed an upregulation in chaperone-mediated autophagy in the hypothalamus of mice fed a high-fat diet for 3 days. Longer exposure to high-fat diet led to the downregulation in hypothalamic chaperone-mediated autophagy. Furthermore, direct exposure of hypothalamic neurons to palmitate, a saturated fatty acid, led to chaperone-mediated autophagy activation. After an insult, the activation of chaperone-mediated autophagy is essential for proteostasis maintenance. On the other hand, failure in this system could lead to increased cellular susceptibility to stressors. Thus, saturated fatty acid excess affects neuronal chaperone-mediated autophagy and this could contribute to neuronal dysfunction and protein aggregate formation in hypothalamic neurons. Therefore, the maintenance of basal chaperone-mediated autophagy levels with pharmacology or dietary interventions could represent an important therapy in the treatment of metabolic disorders (AU) | |
| FAPESP's process: | 13/10911-0 - Modulation of chaperone mediated autophagy in hypothalamus of diet-induced obese mice. |
| Grantee: | Mariana Portovedo de Oliveira Araújo |
| Support Opportunities: | Scholarships in Brazil - Doctorate |