Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus.
Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus.
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DOI：
10.1523/jneurosci.3412-08.2008
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发表时间：
2008-11-19
期刊：
影响因子：
--
通讯作者：
Yeo GS
中科院分区：
文献类型：
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作者：
Tung YC;Ma M;Piper S;Coll A;O'Rahilly S;Yeo GS
瘦素在协调中枢神经系统对营养状态变化的综合反应中起着重要作用。下丘脑室旁核(PVN)内的神经元表达瘦素受体，并接受弓状核中表达瘦素受体的神经元的密集神经支配。为了对循环瘦素对PVN功能的影响有新的认识，我们比较了自由喂养的小鼠和接受假手术或瘦素治疗的48小时禁食小鼠(Ip)激光捕获PVN的整体转录谱。禁食改变了527个PVN表达的基因，这种改变至少被瘦素部分逆转。与以前的报道一致，禁食后促甲状腺激素释放激素mRNA水平降低，但经瘦素治疗后恢复到喂养水平。禁食可降低催产素、加压素和生长抑素的mRNA水平，瘦素可使其恢复。鉴于瘦素对突触重构的已知作用，值得注意的是，在瘦素正调控的前15个基因中，有5个与突触功能和/或可塑性有关(basigin、apoE、GAP43、gabarap和突触核蛋白-γ)。通路分析表明，氧化磷酸化(OXPHOS)，特别是编码在泛醌生物合成中起作用的复合体1蛋白的基因，是以瘦素依赖的方式显著调节的主要基因集。因此，瘦素除了影响多种神经肽的表达外，还可能对室旁核的突触功能和生物能量状态产生更广泛的影响。
Leptin plays a major role in coordinating the integrated response of the central nervous system to changes in nutritional state. Neurons within the paraventricular nucleus (PVN) of the hypothalamus express leptin receptors and receive dense innervation from leptin receptor-expressing neurons in the arcuate nucleus. In order to obtain new insights into the effects of circulating leptin on PVN function, we compared global transcriptional profiles of laser-captured PVN from ad libitum fed mice versus 48 hour fasted mice receiving either sham or leptin treatment intraperitoneally (i.p.). 527 PVN-expressed genes were altered by fasting in a manner which was at least partially reversible by leptin. Consistent with previous reports, thyrotrophin releasing hormone mRNA levels were decreased by fasting but restored to fed levels with leptin treatment. mRNA levels of oxytocin, vasopressin and somatostatin were also reduced by fasting and restored by leptin. Given leptin’s known effects on synaptic remodelling it is notable that among the top fifteen genes that were positively regulated by leptin were five that have been implicated in synaptic function and/or plasticity (basigin, ApoE, Gap43, Gabarap and synuclein-γ). Pathway analysis identified Oxidative Phosphorylation (OXPHOS), in particular, genes encoding complex 1 proteins that play a role in ubiquinone biosynthesis, to be the predominant gene set that was significantly regulated in a leptin dependent manner. Thus, in addition to its effects on the expression of a broad range of neuropeptides, leptin may also exert more general influences on synaptic function in, and the bioenergetic state of, the PVN.