Neuropeptide Y stimulates autophagy in hypothalamic neurons
Neuropeptide Y stimulates autophagy in hypothalamic neurons
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DOI：
10.1073/pnas.1416609112
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发表时间：
2015-03-31
影响因子：
11.1
通讯作者：
Cavadas, Claudia
中科院分区：
文献类型：
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作者：
Aveleira, Celia A.;Botelho, Mariana;Cavadas, Claudia
衰老的特征是自噬损伤，导致与年龄相关的疾病恶化。此外，据描述，下丘脑是全身衰老发展的关键大脑区域，并对寿命产生影响。神经肽Y（neuropeptide Y，NPY）是下丘脑中的主要神经肽之一，并且已经显示，在老年动物中，下丘脑NPY水平降低。由于热量限制（CR）至少部分地通过刺激自噬来延缓衰老，并且还增加下丘脑NPY水平，因此我们假设NPY可能对下丘脑中的自噬调节具有相关作用。因此，本研究的目的是探讨神经肽Y在下丘脑自噬中的作用。利用下丘脑神经元体外模型和下丘脑中过表达NPY的小鼠，我们观察到NPY刺激下丘脑中的自噬。从机制上讲，在啮齿动物下丘脑神经元中，NPY通过激活NPY Y-1和Y-5受体增加自噬，并且这种作用与PI 3 K、MEK/ERK和PKA信号通路的协同激活密切相关。调节下丘脑NPY水平可能被认为是一种潜在的策略，以产生保护作用，对下丘脑损伤与年龄和延缓衰老。
Aging is characterized by autophagy impairment that contributes to age-related disease aggravation. Moreover, it was described that the hypothalamus is a critical brain area for whole-body aging development and has impact on lifespan. Neuropeptide Y (NPY) is one of the major neuropeptides present in the hypothalamus, and it has been shown that, in aged animals, the hypothalamic NPY levels decrease. Because caloric restriction (CR) delays aging, at least in part, by stimulating autophagy, and also increases hypothalamic NPY levels, we hypothesized that NPY could have a relevant role on autophagy modulation in the hypothalamus. Therefore, the aim of this study was to investigate the role of NPY on autophagy in the hypothalamus. Using both hypothalamic neuronal in vitro models and mice overexpressing NPY in the hypothalamus, we observed that NPY stimulates autophagy in the hypothalamus. Mechanistically, in rodent hypothalamic neurons, NPY increases autophagy through the activation of NPY Y-1 and Y-5 receptors, and this effect is tightly associated with the concerted activation of PI3K, MEK/ERK, and PKA signaling pathways. Modulation of hypothalamic NPY levels may be considered a potential strategy to produce protective effects against hypothalamic impairments associated with age and to delay aging.