Carmo-Silva Sara, Cavadas Cláudia
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Adv Neurobiol. 2017;19:73-116. doi: 10.1007/978-3-319-63260-5_4.
The hypothalamus is the brain region responsible for the maintenance of energetic homeostasis. The regulation of this process arises from the ability of the hypothalamus to orchestrate complex physiological responses such as food intake and energy expenditure, circadian rhythm, stress response, and fertility. Metabolic alterations such as obesity can compromise these hypothalamic regulatory functions. Alterations in circadian rhythm, stress response, and fertility further contribute to aggravate the metabolic dysfunction of obesity and contribute to the development of chronic disorders such as depression and infertility.At cellular level, obesity caused by overnutrition can damage the hypothalamus promoting inflammation and impairing hypothalamic neurogenesis. Furthermore, hypothalamic neurons suffer apoptosis and impairment in synaptic plasticity that can compromise the proper functioning of the hypothalamus. Several factors contribute to these phenomena such as ER stress, oxidative stress, and impairments in autophagy. All these observations occur at the same time and it is still difficult to discern whether inflammatory processes are the main drivers of these cellular dysfunctions or if the hypothalamic hormone resistance (insulin, leptin, and ghrelin) can be pinpointed as the source of several of these events.Understanding the mechanisms that underlie the pathophysiology of obesity in the hypothalamus is crucial for the development of strategies that can prevent or attenuate the deleterious effects of obesity.
下丘脑是负责维持能量稳态的脑区。这一过程的调节源于下丘脑协调复杂生理反应的能力，如食物摄入与能量消耗、昼夜节律、应激反应和生育能力。肥胖等代谢改变会损害这些下丘脑调节功能。昼夜节律、应激反应和生育能力的改变进一步加剧肥胖的代谢功能障碍，并导致抑郁症和不孕症等慢性疾病的发生。在细胞水平上，营养过剩导致的肥胖会损害下丘脑，引发炎症并损害下丘脑神经发生。此外，下丘脑神经元会发生凋亡和突触可塑性受损，这会损害下丘脑的正常功能。内质网应激、氧化应激和自噬受损等多种因素导致了这些现象。所有这些观察结果同时出现，目前仍难以确定炎症过程是否是这些细胞功能障碍的主要驱动因素，或者下丘脑激素抵抗（胰岛素、瘦素和胃饥饿素）是否可被确定为其中一些事件的根源。了解下丘脑肥胖病理生理学的潜在机制对于制定能够预防或减轻肥胖有害影响的策略至关重要。
