Nesfatin-1-Regulated Oxytocinergic Signaling in the Paraventricular Nucleus Causes Anorexia through a Leptin-Independent Melanocortin Pathway
Nesfatin-1-Regulated Oxytocinergic Signaling in the Paraventricular Nucleus Causes Anorexia through a Leptin-Independent Melanocortin Pathway
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DOI：
10.1016/j.cmet.2009.09.002
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发表时间：
2009-11-04
期刊：
影响因子：
29
通讯作者：
Yada, Toshihiko
中科院分区：
文献类型：
--
作者：
Maejima, Yuko;Sedbazar, Udval;Yada, Toshihiko
下丘脑室旁核(PVN)作为中枢，整合调节摄食行为的各种神经元活动。Nesfatin-1是新近发现的一种厌食分子，定位于室旁核。然而，Nesfatin-1的厌食神经通路仍不清楚。在这里，我们展示了中央注射Nesfatin-1激活了PVN和脑干孤束核(NTS)。在PVN中，Nesfatin-1靶向于大细胞和小细胞催产素神经元以及Nesfatin-1神经元本身，并刺激催产素的释放。免疫电子显微镜显示Nesfatin-1特异性地存在于PVN神经元的分泌小泡中，而针对内源性Nesfatin-1的免疫中和作用抑制了PVN中催产素的释放，提示Nesfatin-1具有旁分泌/自分泌作用。Nesfatin-1诱导的厌食症可被催产素受体拮抗剂消除。此外，催产素终末与NTS中的阿片黑素皮质素原神经元密切相关，并可激活这些神经元。催产素诱导瘦素抵抗的Zucker肥胖大鼠的黑素皮质素依赖型厌食症。目前的结果揭示了下丘脑室旁核中Nesfatin-1操作的催产素能信号触发瘦素非依赖性黑素皮质素介导的厌食症。
The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.