Selective Deletion of Leptin Receptors in Gonadotropes Reveals Activin and GnRH-Binding Sites as Leptin Targets in Support of Fertility
Selective Deletion of Leptin Receptors in Gonadotropes Reveals Activin and GnRH-Binding Sites as Leptin Targets in Support of Fertility
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DOI：
10.1210/en.2014-1132
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发表时间：
2014-10-01
期刊：
影响因子：
4.8
通讯作者：
Childs, Gwen V.
中科院分区：
文献类型：
--
作者：
Akhter, Noor;CarlLee, Tyler;Childs, Gwen V.
脂肪因子瘦素（LEP）是一种激素通道，向食欲调节神经元发出能量储存的信号，当储存足够时，允许繁殖。LEP受体（LEPR）和促性腺激素或GH的双重标记显示LEPR在发情期增加2倍，其中一些在促性腺激素中可见。因此，我们利用Cre-LoxP技术研究了LEPR在促性腺激素中的功能，利用大鼠Lh - β启动子（Lh - β -cre）驱动的cre -重组酶删除LEPR的信号域（LEPR -外显子17）。器官基因分型、LEPR缺失和促性腺激素突变体对LEP的反应证实了这种缺失的选择性。这种突变对生长、体重、青春期的时间或怀孕都没有影响。突变雌鼠生产第一窝的时间延长了36%，每窝的幼崽数量减少了50%。当研究促性腺激素LEPR缺失对所有垂体激素的广泛影响时，突变雌鼠的血清LH（40%）、FSH（70%）和GH（54%）水平降低，FSH β(59%)和抑制素/激活素β A和β B (25%) mRNA水平降低。突变男性血清GH（74%）、TSH（31%）和催乳素（69%）水平降低，GH（31%）、Ghrhr（30%）、Fsh β(22%)和糖蛋白α亚基（Cga） （22%） mRNA水平降低。血清LEP、ACTH水平及Gnrhr mRNA水平无明显变化。然而，在lepr无效的促性腺激素中，与GnRH受体的结合在女性中分别减少82%或89% (P < 0.0001)，在男性中分别减少27%或53% （P < 0.03）。这与GnRH受体蛋白免疫标记的减少相关，表明LEP的作用可能是转录后的。总的来说，这些研究强调了LEP对gnrh结合位点和激活素作为潜在靶点的促性腺激素的重要性。LEP可以调节人口增长，根据食物供应的可获得性调整后代的数量。
The adipokine, leptin (LEP), is a hormonal gateway, signaling energy stores to appetite-regulatory neurons, permitting reproduction when stores are sufficient. Dual-labeling for LEP receptors (LEPRs) and gonadotropins or GH revealed a 2-fold increase in LEPR during proestrus, some of which was seen in LH gonadotropes. We therefore investigated LEPR functions in gonadotropes with Cre-LoxP technology, deleting the signaling domain of the LEPR (Lepr-exon 17) with Cre-recombinase driven by the rat LH-beta promoter (Lh beta-cre). Selectivity of the deletion was validated by organ genotyping and lack of LEPR and responses to LEP by mutant gonadotropes. The mutation had no impact on growth, body weight, the timing of puberty, or pregnancy. Mutant females took 36% longer to produce their first litter and had 50% fewer pups/litter. When the broad impact of the loss of gonadotrope LEPR on all pituitary hormones was studied, mutant diestrous females had reduced serum levels of LH (40%), FSH (70%), and GH (54%) and mRNA levels of Fsh beta (59%) and inhibin/activin beta A and beta B (25%). Mutant males had reduced serum levels of GH (74%), TSH (31%), and prolactin (69%) and mRNA levels of Gh (31%), Ghrhr (30%), Fsh beta (22%), and glycoprotein alpha-subunit (Cga) (22%). Serum levels of LEP and ACTH and mRNA levels of Gnrhr were unchanged. However, binding to GnRH receptors was reduced in LEPR-null LH or FSH gonadotropes by 82% or 89%, respectively, in females (P < .0001) and 27% or 53%, respectively, in males (P < .03). This correlated with reductions in GnRH receptor protein immunolabeling, suggesting that LEP's actions may be posttranscriptional. Collectively, these studies highlight the importance of LEP to gonadotropes with GnRH-binding sites and activin as potential targets. LEP may modulate population growth, adjusting the number of offspring to the availability of food supplies.