Control of GnRH neuronal activity by metabolic factors: The role of leptin and insulin
Control of GnRH neuronal activity by metabolic factors: The role of leptin and insulin
复制标题
DOI：
10.1016/j.mce.2006.04.023
复制
发表时间：
2006-07-25
影响因子：
4.1
通讯作者：
Pralong, Francois P.
中科院分区：
文献类型：
--
作者：
Gamba, Marcella;Pralong, Francois P.
能量平衡对生殖功能有着至关重要的影响。瘦素和胰岛素是向下丘脑发出个体营养状态信号的代谢因子之一，并且它们在GnRH神经元活性的整体调节中的作用越来越被认识到。本文所述的实验旨在进一步研究这两种激素的中枢作用机制以及它们对生殖轴的作用所涉及的精确的下丘脑通路。NPY神经元代表下丘脑内瘦素作用的主要靶点。探讨下丘脑NPY神经元系统及其下游信号通路在瘦素生殖效应中的重要作用。结果表明，NPY Y1受体在控制青春期的开始和瘦素维持生殖功能中起着至关重要的作用。这些实验的一个惊人的发现是观察到，服从食物限制的幼年Y1（-/-）小鼠可以像正常喂养的动物一样经历青春期，这表明Y1的缺乏损害了对促性腺激素轴能量储存减少的感知。我们使用了平行的体内和体外实验来描述胰岛素在刺激和维持细胞活性中的作用。神经内分泌生殖轴首先，我们观察到在正常雄性小鼠的高胰岛素钳夹研究中循环胰岛素水平的增加与LH分泌的显著增加相关。胰岛素的这种作用可能在下丘脑水平介导，因为胰岛素刺激培养的下丘脑神经元分泌和表达GnRH。使用原代神经元培养物以及一种新的GnRH神经元细胞系获得的条件永生化的成年大鼠下丘脑神经元，我们最近已经证明，这种影响胰岛素对GnRH基因表达可能是直接介导的GnRH神经元的水平，并涉及刺激的MAP激酶Erk 1/2途径。两者合计，这些结果提供了新的见解参与的机制，通过代谢因素的调节GnRH神经元的活动。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Energy balance exerts a critical influence on reproductive function. Leptin and insulin are among the metabolic factors signaling the nutritional status of an individual to the hypothalamus, and their role in the overall modulation of the activity of GnRH neurons is increasingly recognized. The experiments described here were designed to further investigate the central mechanisms of action of these two hormones and the precise hypothalamic pathways implicated in their effects on the reproductive axis.NPY neurons represent a primary target of leptin actions within the hypothalamus We used mice lacking the NPY Y1 receptor (Y1(-/-) mice) to investigate the physiological importance of the hypothalamic NPY neuronal system and its downstream pathways involving Y1 in the reproductive effects of leptin. Results point to a crucial role for the NPY Y1 receptor in the control of the onset of puberty and the maintenance of reproductive functions by leptin. A striking finding of these experiments was the observation that juvenile Y1(-/-) mice submitted to food restriction can proceed through puberty like normally fed animals, demonstrating that the absence of Y1 impairs the perception of decreasing energy stores by the gonadotrope axis.Next, we used parallel in vivo and in vitro experiments to delineate the role of insulin in the stimulation and maintenance of the activity of the neuroendocrine reproductive axis. First, we observed that the increase in circulating insulin levels achieved during hyperinsulinemic clamp studies in normal male mice was associated with a significant rise in LH secretion. This effect of insulin is likely mediated at the hypothalamic level, as insulin stimulates the secretion and the expression of GnRH by hypothalamic neurons in culture. Using primary neuronal cultures as well as a novel GnRH neuronal cell line obtained by conditional immortalization of adult rat hypothalamic neurons, we have recently demonstrated that this effect of insulin on GnRH gene expression is probably mediated directly at the level of GnRH neurons, and involves the stimulation of the MAP kinase Erk1/2 pathway. Taken together, these results provide new insights into the mechanisms involved in the regulation of GnRH neuronal activity by metabolic factors. (c) 2006 Elsevier Ireland Ltd. All rights reserved.