Leptin-induced nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei involved in body weight regulation
Leptin-induced nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei involved in body weight regulation
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DOI：
10.1523/jneurosci.21-07-02413.2001
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发表时间：
2001-04-01
影响因子：
5.3
通讯作者：
Meyerhof, W
中科院分区：
文献类型：
--
作者：
Hübschle, T;Thom, E;Meyerhof, W
瘦素参与下丘脑对食物摄入和体重的控制。Fos免疫组织化学已被用于对参与这些调节过程的瘦素靶神经元进行功能定位。然而，在瘦素刺激后，只有一部分表达瘦素受体长型（Ob - Rb）的下丘脑神经元也共同表达神经元激活标志物Fos。为了对所有瘦素靶神经元进行功能定位，无论瘦素介导的是神经元激活还是抑制，我们通过免疫组织化学方法研究了瘦素诱导的信号转导和转录激活因子STAT3的核转位，这是瘦素依赖性基因表达调控的关键步骤。通过与核4',6 - 二脒基 - 2 - 苯基吲哚二乳酸盐染色的共定位研究证明，脑室内给予瘦素处理（而非脑室内给予无热原生理盐水）可诱导下丘脑核中STAT3免疫反应性呈时间依赖性的核转位，在弓状核、下丘脑外侧区以及下丘脑腹内侧核和背内侧核中可检测到强烈的核STAT3信号。这种瘦素诱导的STAT3转位模式与白细胞介素 - 6（另一种在其信号通路中使用STAT3的细胞因子）诱导的模式不同。瘦素处理后联合进行STAT3和Fos的免疫组织化学检测显示，在上述下丘脑结构中，STAT3阳性细胞核的数量多于Fos阳性细胞核，并且表明Fos免疫反应性仅在所有对瘦素有反应的STAT3细胞核的一部分中存在共定位。这些结果表明，检测核STAT3免疫反应性是一种对中枢瘦素作用进行功能定位的新型神经解剖学工具。它们进一步支持了位于腹侧的下丘脑尾部结构的重要性，这些结构是参与体重调节的主要瘦素靶点。
Leptin is involved in the hypothalamic control of food intake and body weight. Fos immunohistochemistry has been used to functionally map leptin target neurons involved in these regulatory processes. However, only a subset of hypothalamic neurons expressing the long form of the leptin receptor (Ob-Rb) also coexpress the neuronal activation marker Fos after leptin stimulation. To functionally map all leptin target neurons, regardless of whether leptin-mediated neuronal activation or inhibition occurs, we immunohistochemically investigated the leptin-induced nuclear translocation of the signal transducer and activator of transcription molecule STAT3, which represents a crucial step in the regulation of leptin-dependent gene expression. As proven by colocalization studies with the nuclear 4',6-diamidino-2-phenylindole dilactate stain, intracerebroventricular leptin treatment, but not intracerebroventricular application of pyrogen-free saline, induced a time-dependent nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei, with strong nuclear STAT3 signals detectable in the arcuate nucleus, the lateral hypothalamus, and the ventro-medial and dorsomedial hypothalamic nuclei. This leptin-induced STAT3 translocation pattern proved to be distinct from that induced by interleukin-6, another cytokine using STAT3 in its signaling pathway. Combined immunohistochemical STAT3 and Fos detection after leptin treatment revealed a higher number of STAT3-positive than Fos-positive cell nuclei in the aforementioned hypothalamic structures and showed that Fos immunoreactivity colocalized only in a subset of all leptin-responsive STAT3 nuclei. These results suggest that the detection of nuclear STAT3 immunoreactivity represents a new neuroanatomical tool to functionally map central leptin actions. They further support the importance of ventrally located caudal hypothalamic structures representing the main leptin targets involved in body weight regulation.