Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-504, Portugal.
Faculty of Pharmacy, University of Coimbra, Coimbra, 3004-504, Portugal.
Nat Rev Endocrinol. 2016 Dec;12(12):723-733. doi: 10.1038/nrendo.2016.107. Epub 2016 Jul 8.
Hypothalamic dysfunction has emerged as an important mechanism involved in the development of obesity and its comorbidities, as well as in the process of ageing and age-related diseases, such as type 2 diabetes mellitus, hypertension and Alzheimer disease. In both obesity and ageing, inflammatory signalling is thought to coordinate many of the cellular events that lead to hypothalamic neuronal dysfunction. This process is triggered by the activation of signalling via the toll-like receptor 4 pathway and endoplasmic reticulum stress, which in turn results in intracellular inflammatory signalling. However, the process that connects inflammation with neuronal dysfunction is complex and includes several regulatory mechanisms that ultimately control the homeostasis of intracellular proteins and organelles (also known as 'proteostasis'). This Review discusses the evidence for the key role of proteostasis in the control of hypothalamic neurons and the involvement of this process in regulating whole-body energy homeostasis and lifespan.
下丘脑功能障碍已成为肥胖及其合并症、衰老和与年龄相关疾病（如 2 型糖尿病、高血压和阿尔茨海默病）发展的重要机制。在肥胖和衰老中，炎症信号被认为协调了许多导致下丘脑神经元功能障碍的细胞事件。这个过程是由 Toll 样受体 4 途径和内质网应激激活的信号转导触发的，进而导致细胞内炎症信号转导。然而，将炎症与神经元功能障碍联系起来的过程是复杂的，包括几个调节机制，这些机制最终控制细胞内蛋白质和细胞器的内稳态（也称为“蛋白稳态”）。本综述讨论了蛋白稳态在控制下丘脑神经元中的关键作用的证据，以及该过程在调节全身能量平衡和寿命中的参与。
