Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus
Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus
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DOI：
10.1210/en.138.6.2569
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发表时间：
1997-06-01
期刊：
影响因子：
4.8
通讯作者：
Lechan, RM
中科院分区：
文献类型：
--
作者：
Legradi, G;Emerson, CH;Lechan, RM
长时间禁食与甲状腺轴的一些变化有关，表现为血清T-3和T-4水平低，而矛盾的是，TSH低或正常。这种反应至少部分是由于下丘脑室旁核（PVN）神经元中突起h基因表达的抑制和下丘脑TRH释放的减少。由于全身给药瘦素可以减弱小鼠甲状腺激素水平的下降，因此我们提出瘦素可能在甲状腺轴的神经内分泌调节中发挥重要作用，通过影响垂体性神经元产生progh。成年雄性Sprague-Dawley大鼠正常喂养，禁食3天，或禁食并每6小时给药0.5 μ g/gm BW。与对照组相比，禁食动物血浆总T-4和游离T-4水平显著降低，并通过给药恢复到正常水平。在禁食期间，游离T-4的百分比增加，而游离T-3的百分比没有增加，这进一步表明，在瘦素给药后，血浆转甲状腺素水平没有恢复到进食水平。通过原位杂交放射自显像半定量分析发现，禁食动物内侧旁细胞PVN神经元的shrh信使RNA明显受到抑制，但瘦素给药后恢复正常[喂食vs快速vs快速/瘦素（密度单位× 10(8)）： 8.5 +/- 0.4, 3.2 +/- 0.2, 8.1 +/- 0.8]。相比之下，下丘脑外侧相邻神经元中不具有垂体功能的突起h信使RNA在任何实验操作下都保持不变。这些发现表明瘦素具有选择性的中枢作用，通过调节PVN中的progh基因表达来调节下丘脑-垂体-甲状腺轴，但对甲状腺结合蛋白没有外周作用。我们提出，禁食期间循环瘦素水平的下降重置了甲状腺激素对促垂体肽生物合成的反馈抑制的设定点，从而允许适应饥饿。
Prolonged fasting is associated with a number of changes in the thyroid axis manifested by low serum T-3 and T-4 levels and, paradoxically, low or normal TSH. This response is, at least partly, caused by suppression of proTRH gene expression in neurons of the hypothalamic paraventricular nucleus (PVN) and reduced hypothalamic TRH release. Because the fall in thyroid hormone levels can be blunted in mice by the systemic administration of leptin, we raised the possibility that leptin may have an important role in the neuroendocrine regulation of the thyroid axis, through effects on hypophysiotropic neurons producing proTRH. Adult male, Sprague-Dawley rats were either fed normally, fasted for 3 days, or fasted and administered leptin at a dose of 0.5 mu g/gm BW ip every 6 h. Fasted animals showed significant reduction in plasma total and free T-4 and T-3 levels compared with controls, that were restored toward normal by the administration of leptin. Percent free T-4, but not percent free T-3, increased during fasting, further suggesting a reduction in plasma transthyretin levels that did not return to fed levels after leptin administration. By semiquantitative analysis of in situ hybridization autoradiograms, proTRH messenger RNA in medial parvocellular PVN neurons was markedly suppressed in the fasting animals but was restored to normal by leptin administration [fed vs. fast vs. fast/leptin (density units x 10(8)): 8.5 +/- 0.4, 3.2 +/- 0.2, 8.1 +/- 0.8]. In contrast, proTRH messenger RNA in adjacent neurons in the lateral hypothalamus that do not have a hypophysiotropic function remained unchanged by any of the experimental manipulations. These findings indicate that leptin has a selective, central action to modulate the hypothalamic-pituitary-thyroid axis by regulating proTRH gene expression in the PVN but does not have peripheral effects on thyroid-binding proteins. We propose that the fall in circulating leptin levels during fasting resets the set point for feedback inhibition by thyroid hormones on the biosynthesis of hypophysiotropic proTRH, thereby allowing adaptation to starvation.