Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
J Neurosci. 2010 Jun 9;30(23):7783-92. doi: 10.1523/JNEUROSCI.5828-09.2010.
The hypothalamic peptide, nesfatin-1, derived from the precursor NEFA/nucleobindin 2 (NUCB2), was recently identified as anorexigenic signal, acting in a leptin-independent manner. Yet its participation in the regulation of other biological functions gated by body energy status remains unexplored. We show herein that NUCB2/nesfatin-1 is involved in the control of female puberty. NUCB2/nesfatin mRNA and protein were detected at the hypothalamus of pubertal female rats, with prominent signals at lateral hypothalamus (LHA), paraventricular (PVN), and supraoptic (SON) nuclei. Hypothalamic NUCB2 expression raised along pubertal transition, with detectable elevations of its mRNA levels at LHA, PVN, and SON, and threefold increase of its total protein content between late-infantile and peripubertal periods. Conditions of negative energy balance, such as 48 h fasting or sustained subnutrition, decreased hypothalamic NUCB2 mRNA and/or protein levels in pubertal females. At this age, central administration of nesfatin-1 induced modest but significant elevations of circulating gonadotropins, whose magnitude was notably augmented in conditions of food deprivation. Continuous intracerebroventricular infusion of antisense morpholino oligonucleotides (as-MONs) against NUCB2 along pubertal maturation, which markedly reduced hypothalamic NUCB2 protein content, delayed vaginal opening and decreased ovarian weights and serum luteinizing hormone (LH) levels. In contrast, in adult female rats, intracerebroventricular injection of nesfatin did not stimulate LH or follicle-stimulating hormone secretion; neither did central as-MON infusion alter preovulatory gonadotropin surges, despite suppression of hypothalamic NUCB2. In sum, our data are the first to disclose the indispensable role of NUCB2/nesfatin-1 in the central networks driving puberty onset, a function that may contribute to its functional coupling to energy homeostasis.
下丘脑中的肽类激素 nesfatin-1 来源于前体蛋白 NEFA/nucleobindin 2（NUCB2），最近被鉴定为一种具有抗食欲作用的信号分子，其作用方式与瘦素无关。然而，其在调节其他与身体能量状态相关的生物学功能中的作用尚未被探索。本文研究表明，NUCB2/nesfatin-1 参与了雌性青春期的调控。在青春期雌性大鼠的下丘脑可检测到 NUCB2/nesfatin mRNA 和蛋白，在下丘脑外侧核（LHA）、室旁核（PVN）和视上核（SON）有明显信号。NUCB2 在下丘脑的表达随着青春期的转变而增加，在 LHA、PVN 和 SON 中可检测到其 mRNA 水平的升高，在婴儿后期到青春期之间其总蛋白含量增加了三倍。负能平衡状态，如 48 小时禁食或持续半饥饿，会降低青春期雌性大鼠下丘脑 NUCB2 mRNA 和/或蛋白水平。在这个年龄，nesfatin-1 的中枢给药会引起循环促性腺激素的适度但显著升高，而在禁食的情况下其幅度明显增加。在青春期成熟过程中，连续脑室内输注针对 NUCB2 的反义 morpholino 寡核苷酸（as-MONs），会显著降低下丘脑 NUCB2 蛋白含量，延迟阴道开口，减少卵巢重量和血清促黄体生成素（LH）水平。相反，在成年雌性大鼠中，脑室内注射 nesfatin 不会刺激 LH 或卵泡刺激素的分泌；中枢注射 as-MON 也不会改变促性腺激素的排卵前激增，尽管抑制了下丘脑 NUCB2。总之，我们的数据首次揭示了 NUCB2/nesfatin-1 在驱动青春期启动的中枢网络中不可或缺的作用，这一功能可能与其与能量稳态的功能耦合有关。
