Agouti-related peptide plays a critical role in leptin's effects on female puberty and reproduction.
Agouti-related peptide plays a critical role in leptin's effects on female puberty and reproduction.
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DOI：
10.1152/ajpendo.00241.2013
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发表时间：
2013-12
期刊：
影响因子：
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通讯作者：
Sharone Sheffer-Babila;Yan Sun;D. Israel;Shun-Mei Liu;G. Neal-Perry;S. Chua
中科院分区：
文献类型：
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作者：
Sharone Sheffer-Babila;Yan Sun;D. Israel;Shun-Mei Liu;G. Neal-Perry;S. Chua
瘦素信号缺陷通过GnRH神经元活性降低导致不育，导致啮齿动物和人类的性腺功能低下。由于GnRH神经元不表达瘦素受体，瘦素对GnRH神经元的作用必然是间接的。下丘脑弓状核内共同表达AGRP和NPY的神经元被认为是参与瘦素调节GnRH神经元的重要中间神经元。在此之前，我们曾报道过瘦素受体突变(Lepr(db/db))女性的AGRP缺失和MC4R单倍体缺失可导致生育和哺乳的恢复，尽管肥胖和胰岛素抵抗持续存在。本研究的主要假设是，在瘦素信号缺乏的情况下，缺乏或减少瘦素对AGRP/NPY神经元的抑制会导致GnRH的释放受到抑制。由于Tac2(NKB)-TAC3R信号在青春期成熟过程中起作用，并受代谢状态的调节，本研究的另一个目的是检测ARC中受黑素皮质素能信号调控的Tac2/NKB神经元是否影响瘦素对青春期和生殖的作用。我们的数据显示，LEPR(db/db)女性的AGRP缺乏可以恢复正常的阴道张开和发情周期，尽管子宫重量增加和乳腺发育在形态上被推迟。尽管如此，AgRP(-/-)Lepr(db/db)雌性是有生育能力的，并能维持哺乳至断奶幼崽的充足营养。AgRP缺乏会导致野生型雌性小鼠阴道提前开放。LepR(db/db)雌性下丘脑Tac2基因在青春期后未见增加，而AGRP缺乏则使LepR(db/db)雌性恢复正常。此外，用MTII激活MC4R可诱导Tac2神经元FOS的表达，支持Tac2神经元的黑素皮质能调节的概念。这些研究表明，AGRP对青春期有抑制作用，Tac2神经元可能通过传递对GnRH神经元的黑素皮质素能抑制作用。
Deficient leptin signaling causes infertility via reduced activity of GnRH neurons, causing a hypogonadal state in both rodents and humans. Because GnRH neurons do not express leptin receptors, leptin's effect on GnRH neurons must be indirect. Neurons within the hypothalamic arcuate nucleus that coexpress AGRP and NPY are considered to be important intermediate neurons involved in leptin regulation of GnRH neurons. Previously, we reported that the absence of AGRP and haploinsufficiency of MC4R in leptin receptor mutant (Lepr(db/db)) females result in restoration of fertility and lactation despite the persistence of obesity and insulin resistance. The overarching hypothesis in the present study is that the absence or reduction of leptin's inhibition of AGRP/NPY neurons leads to suppression of GnRH release in cases of leptin signaling deficiency. Since TAC2 (NKB)-TAC3R signaling plays a role in puberty maturation and is modulated by metabolic status, the other aim of this study is to test whether TAC2/NKB neurons in ARC regulated by melanocortinergic signals herein affect leptin's action on puberty and reproduction. Our data showed that AGRP deficiency in Lepr(db/db) females restores normal timing of vaginal opening and estrous cycling, although uterine weight gain and mammary gland development are morphologically delayed. Nonetheless, Agrp(-/-) Lepr(db/db) females are fertile and sustain adequate nutrition of pups with lactation to weaning age. AGRP deficiency results in advanced vaginal opening in wild-type female mice. The postpubertal increase in hypothalamic TAC2 mRNA was not observed in Lepr(db/db) females, whereas AGRP deficiency restored it in Lepr(db/db) females. Additionally, MC4R activation with MTII induced FOS expression in TAC2 neurons, supporting the concept of melanocortinergic regulation of TAC2 neurons. These studies suggest that AGRP imposes an inhibitory effect on puberty and that TAC2 neurons may transmit melanocortinergic inhibition of GnRH neurons.