Department of Physiology, Monash University, Clayton, Victoria, Australia.
Endocrinology. 2010 May;151(5):2106-16. doi: 10.1210/en.2009-1283. Epub 2010 Mar 22.
It is widely accepted that leptin acts on first-order neurons in the arcuate nucleus (ARC) with information then relayed to other hypothalamic centers. However, the extent to which leptin mediates its central actions solely, or even primarily, via this route is unclear. We used a model of hypothalamo-pituitary disconnection (HPD) to determine whether leptin action on appetite-regulating systems requires the ARC. This surgical preparation eliminates the ARC. We measured effects of iv leptin to activate hypothalamic neurons (Fos labeling). In ARC-intact animals, leptin increased the percentage of Fos-positive melanocortin neurons and reduced percentages of Fos-positive neuropeptide Y neurons compared with saline-treated animals. HPD itself increased Fos labeling in the lateral hypothalamic area (LHA). Leptin influenced Fos labeling in the dorsomedial nucleus (DMH), ventromedial nucleus, and paraventricular nucleus (PVN) in HPD and normal animals, with effects on particular cell types varying. In the LHA and DMH, leptin decreased orexin cell activation in HPD and ARC-intact sheep. HPD abolished leptin-induced expression of Fos in melanin-concentrating hormone cells in the LHA and in CRH cells in the PVN. In contrast, HPD accentuated activation in oxytocin neurons. Our data from sheep with lesions encompassing the ARC do not suggest a primacy of action of leptin in this nucleus. We demonstrate that first order to second order signaling may not represent the predominant means by which leptin acts in the brain to generate integrated responses. We provide evidence that leptin exerts direct action on cells of the DMH, ventromedial nucleus, and PVN.
人们普遍认为，瘦素作用于弓状核（ARC）中的一级神经元，然后将信息传递到其他下丘脑中枢。然而，瘦素通过这种途径介导其中枢作用的程度尚不清楚，无论是完全还是主要通过这种途径。我们使用下丘脑-垂体分离（HPD）模型来确定瘦素对调节食欲的系统的作用是否需要 ARC。这种手术准备消除了 ARC。我们测量了 iv 瘦素激活下丘脑神经元的效果（Fos 标记）。在 ARC 完整的动物中，与盐水处理的动物相比，瘦素增加了 Fos 阳性黑色素浓缩激素神经元的百分比，并减少了 Fos 阳性神经肽 Y 神经元的百分比。HPD 本身增加了外侧下丘脑区域（LHA）的 Fos 标记。瘦素影响了 HPD 和正常动物的背内侧核（DMH）、腹内侧核和室旁核（PVN）中的 Fos 标记，对特定细胞类型的影响不同。在 LHA 和 DMH 中，瘦素降低了 HPD 和 ARC 完整绵羊中食欲素细胞的激活。HPD 消除了 LHA 中瘦素诱导的黑色素浓缩激素细胞和 PVN 中 CRH 细胞中 Fos 的表达。相比之下，HPD 增强了催产素神经元的激活。我们对包括 ARC 在内的病变羊的数据表明，瘦素在该核中的作用不是首要的。我们证明，第一级到第二级信号传递可能不是瘦素在大脑中产生整合反应的主要作用方式。我们提供的证据表明，瘦素对 DMH、腹内侧核和 PVN 的细胞直接起作用。
