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| Author(s): |
Leticia Ignácio de Souza Zimmermann
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2013-05-02 |
| Examining board members: |
Licio Augusto Velloso;
Adriana Souza Torsoni;
Carmen Veríssima Ferreira;
Fernanda Ortis;
Márcia Queiroz Latorraca
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| Advisor: | Licio Augusto Velloso; Marciane Milanski |
| Abstract | |
The consumption of high-fat diets, especially those rich in saturated fatty acids, plays the most important role in the development of obesity. Recent studies by several groups, including ours, have shown that dietary long-chain saturated fatty acids lead to the development of hypothalamic resistance to leptin and insulin, an important condition contributing for breaking of the balance between caloric intake and energy expenditure. Two molecular mechanisms are currently known to play a triggering role in this process; activation of TLR4 and endoplasmic reticulum stress, both leading to local inflammation and eventually apoptosis of neurons. The ubiquitin-proteasome system (UPS) plays an important role in the control of protein recycling in the cell. The accumulation of ubiquitin-positive protein aggregates can cause cell toxicity and regulate neuronal plasticity. Also the modulation or differential activation of UPS can produce hypothalamic neurodegeneration and obese phenotype in experimental animals. Here, we hypothesized that under prolonged diet-induced obesity, a defect in the UPS in the hypothalamus could contribute for the defective control of energy homeostasis leading to the refractoriness of obesity to caloric restriction. In fact in an obesity-prone rodent strain, prolonged, but not short-term obesity was accompanied by functional abnormality of the UPS in the hypothalamus. In mutants protected from inflammation, resistance to diet-induced obesity was accompanied by stability of the UPS in the hypothalamus. Thus, defect of the UPS in the hypothalamus, during prolonged obesity is an important factor contributing the refractoriness of obesity to caloric restriction (AU) | |