Foradori Chad D, Whitlock Brian K, Daniel Jay A, Zimmerman Arthur D, Jones Melaney A, Read Casey C, Steele Barbara P, Smith Jeremy T, Clarke Iain J, Elsasser Theodore H, Keisler Duane H, Sartin James L
Department of Anatomy, Physiology & Pharmacology, Auburn University, Auburn, Alabama 36849.
Department of Large Animal Clinical Sciences, University of Tennessee, Knoxville, Tennessee 37996.
Endocrinology. 2017 Oct 1;158(10):3526-3539. doi: 10.1210/en.2017-00303.
Although kisspeptin is the primary stimulator of gonadotropin-releasing hormone secretion and therefore the hypothalamic-pituitary-gonadal axis, recent findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Here we show that central delivery of kisspeptin causes a robust rise in plasma GH in fasted but not fed sheep. Kisspeptin-induced GH secretion was similar in animals fasted for 24 hours and those fasted for 72 hours, suggesting that the factors involved in kisspeptin-induced GH secretion are responsive to loss of food availability and not the result of severe negative energy balance. Pretreatment with the neuropeptide Y (NPY) Y1 receptor antagonist, BIBO 3304, blocked the effects of kisspeptin-induced GH release, implicating NPY as an intermediary. Kisspeptin treatment induced c-Fos in NPY and GH-releasing hormone (GHRH) cells of the arcuate nucleus. The same kisspeptin treatment resulted in a reduction in c-Fos in somatostatin (SS) cells in the periventricular nucleus. Finally, blockade of systemic ghrelin release or antagonism of the ghrelin receptor eliminated or reduced the ability of kisspeptin to induce GH release, suggesting the presence of ghrelin is required for kisspeptin-induced GH release in fasted animals. Our findings support the hypothesis that during short-term fasting, systemic ghrelin concentrations and NPY expression in the arcuate nucleus rise. This permits kisspeptin activation of NPY cells. In turn, NPY stimulates GHRH cells and inhibits SS cells, resulting in GH release. We propose a mechanism by which kisspeptin conveys reproductive and hormone status onto the somatotropic axis, resulting in alterations in GH release.
尽管 kisspeptin 是促性腺激素释放激素分泌的主要刺激因子，因此也是下丘脑 - 垂体 - 性腺轴的主要刺激因子，但最近的研究结果表明，kisspeptin 还可以调节包括生长激素（GH）释放在内的其他神经内分泌过程。在这里，我们表明，向禁食但非进食的绵羊中枢递送 kisspeptin 会导致血浆 GH 显著升高。在禁食 24 小时的动物和禁食 72 小时的动物中，kisspeptin 诱导的 GH 分泌相似，这表明 kisspeptin 诱导 GH 分泌所涉及的因素对食物供应的丧失有反应，而不是严重负能量平衡的结果。用神经肽 Y（NPY）Y1 受体拮抗剂 BIBO 3304 预处理可阻断 kisspeptin 诱导的 GH 释放作用，表明 NPY 是一个中介物。kisspeptin 处理诱导弓状核中 NPY 和生长激素释放激素（GHRH）细胞中的 c-Fos。相同的 kisspeptin 处理导致室旁核中生长抑素（SS）细胞中的 c-Fos 减少。最后，全身胃饥饿素释放的阻断或胃饥饿素受体的拮抗消除或降低了 kisspeptin 诱导 GH 释放的能力，这表明在禁食动物中，胃饥饿素的存在是 kisspeptin 诱导 GH 释放所必需的。我们的研究结果支持这样的假设，即在短期禁食期间，全身胃饥饿素浓度和弓状核中 NPY 的表达会升高。这使得 kisspeptin 能够激活 NPY 细胞。反过来，NPY 刺激 GHRH 细胞并抑制 SS 细胞，从而导致 GH 释放。我们提出了一种机制，通过该机制 kisspeptin 将生殖和激素状态传递到生长激素轴上，从而导致 GH 释放的改变。
