FoxO3a, a forkhead family member of transcription factors, is involved in the regulation of cell metabolism, proliferation, differentiation and apoptosis. However, whether FoxO3a participates in the regulation of glucocorticoids induced-hypothalamic-pituitary-adrenal (HPA) dysfunction is still unknown. Our present results indicate that dexamethasone(DEX) increased FoxO3a expression in PC12 and hypothalamic neuronal cultures in correlation to reduced expression of NPW, a process that could be blocked by GR2 antagonist. DEX restrained the phosphorylation of Akt and FoxO3a, but not ERK1/2 phosphorylation, resulting with FoxO3a nuclear localization. Overexpression of FoxO3a inhibited NPW expression, while FoxO3a knockdown by siRNA had the opposite effect. The regulatory region of NPW promoter contains multiple FoxO3a binding sites, and FoxO3a bonding to these sites inhibited its transcriptional activity. In a rat model, chronic administration of corticosterone reduced animals' body weight and sucrose consumption and caused stress- depression like behavior. Corticosterone treatment induced a marked increase in FoxO3a levels, while decreased the expression of NPW protein in the hypothalamus. Immunofluorescent double labeling demonstrated that FoxO3a and NPW were collocated in the hypothalamus. Taken together, these data indicate that NPW is a new direct downstream target gene of FoxO3a. FoxO3a suppressed the transcription of NPW and modulated glucocorticoids-induced HPA dysfunction by directly regulating the expression of NPW. Thus, present findings suggest that FoxO3a and NPW may be potential therapeutic targets for endocrine and psychiatric disorders.

中文翻译：

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FoxO3a 抑制神经元细胞和大鼠下丘脑中神经肽 W 的表达及其对下丘脑-垂体-肾上腺 (HPA) 轴的影响

FoxO3a是转录因子的叉头家族成员，参与细胞代谢、增殖、分化和凋亡的调节。然而，FoxO3a 是否参与糖皮质激素诱导的下丘脑-垂体-肾上腺 (HPA) 功能障碍的调节尚不清楚。我们目前的结果表明，地塞米松 (DEX) 增加了 PC12 和下丘脑神经元培养物中 FoxO3a 的表达，这与 NPW 的表达降低有关，这一过程可以被 GR2 拮抗剂阻断。DEX 抑制 Akt 和 FoxO3a 的磷酸化，但不抑制 ERK1/2 磷酸化，导致 FoxO3a 核定位。FoxO3a 的过表达抑制了 NPW 的表达，而 siRNA 敲低 FoxO3a 的效果相反。NPW 启动子的调控区包含多个 FoxO3a 结合位点，与这些位点结合的 FoxO3a 抑制了其转录活性。在大鼠模型中，长期服用皮质酮会降低动物的体重和蔗糖消耗，并导致类似压力抑郁的行为。皮质酮治疗诱导 FoxO3a 水平显着增加，同时降低下丘脑 NPW 蛋白的表达。免疫荧光双标记表明 FoxO3a 和 NPW 位于下丘脑中。总之，这些数据表明NPW是FoxO3a的一个新的直接下游靶基因。FoxO3a 通过直接调节 NPW 的表达来抑制 NPW 的转录并调节糖皮质激素诱导的 HPA 功能障碍。因此，目前的研究结果表明，FoxO3a 和 NPW 可能是内分泌和精神疾病的潜在治疗靶点。