Department of Pathology and the Evelyn F. McKnight Brain Institute, University of Arizona College of Medicine, Tucson, Arizona 85724, USA.
Endocrinology. 2012 Jun;153(6):2800-12. doi: 10.1210/en.2012-1045. Epub 2012 Apr 16.
Estrogen withdrawal increases gonadotropin secretion and body weight, but the critical cell populations mediating these effects are not well understood. Recent studies have focused on a subpopulation of hypothalamic arcuate neurons that coexpress estrogen receptor α, neurokinin 3 receptor (NK(3)R), kisspeptin, neurokinin B, and dynorphin for the regulation of reproduction. To investigate the function of kisspeptin/neurokinin B/dynorphin (KNDy) neurons, a novel method was developed to ablate these cells using a selective NK(3)R agonist conjugated to the ribosome-inactivating toxin, saporin (NK(3)-SAP). Stereotaxic injections of NK(3)-SAP in the arcuate nucleus ablated KNDy neurons, as demonstrated by the near-complete loss of NK(3)R, NKB, and kisspeptin-immunoreactive (ir) neurons and depletion of the majority of arcuate dynorphin-ir neurons. Selectivity was demonstrated by the preservation of proopiomelanocortin, neuropeptide Y, and GnRH-ir elements in the arcuate nucleus and median eminence. In control rats, ovariectomy (OVX) markedly increased serum LH, FSH, and body weight, and these parameters were subsequently decreased by treatment with 17β-estradiol. KNDy neuron ablation prevented the rise in serum LH after OVX and attenuated the rise in serum FSH. KNDy neuron ablation did not completely block the suppressive effects of E(2) on gonadotropin secretion, a finding consistent with redundant pathways for estrogen negative feedback. However, regardless of estrogen status, KNDy-ablated rats had lower levels of serum gonadotropins compared with controls. Surprisingly, KNDy neuron ablation prevented the dramatic effects of OVX and 17β-estradiol (E(2)) replacement on body weight and abdominal girth. These data provide evidence that arcuate KNDy neurons are essential for tonic gonadotropin secretion, the rise in LH after removal of E(2), and the E(2) modulation of body weight.
雌激素撤退会增加促性腺激素的分泌和体重，但介导这些效应的关键细胞群体尚未得到很好的理解。最近的研究集中在表达雌激素受体 α、神经激肽 3 受体 (NK3R)、促 kisspeptin、神经激肽 B 和强啡肽的下丘脑弓状核神经元亚群上，用于调节生殖。为了研究 kisspeptin/神经激肽 B/强啡肽 (KNDy) 神经元的功能，开发了一种使用与核糖体失活毒素连接的选择性 NK3R 激动剂 (NK3-SAP) 来消融这些细胞的新方法。在弓状核内立体定向注射 NK3-SAP 可消融 KNDy 神经元，表现为 NK3R、NKB 和 kisspeptin-免疫反应 (ir) 神经元几乎完全丢失，以及大多数弓状 dynorphin-ir 神经元耗竭。通过保留弓状核和正中隆起中的 proopiomelanocortin、神经肽 Y 和 GnRH-ir 元件，证明了选择性。在对照大鼠中，卵巢切除术 (OVX) 显著增加了血清 LH、FSH 和体重，这些参数随后通过用 17β-雌二醇处理而降低。KNDy 神经元消融可防止 OVX 后血清 LH 的升高，并减弱血清 FSH 的升高。KNDy 神经元消融并没有完全阻断雌激素对促性腺激素分泌的负反馈抑制作用，这一发现与雌激素负反馈的冗余途径一致。然而，无论雌激素状态如何，KNDy 消融大鼠的血清促性腺激素水平均低于对照组。令人惊讶的是，KNDy 神经元消融可防止 OVX 和 17β-雌二醇 (E2) 替代对体重和腹部周长的显著影响。这些数据提供了证据，证明弓状核 KNDy 神经元是维持促性腺激素分泌、雌激素去除后 LH 升高以及 E2 调节体重的必要条件。
