Physiology Section, Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of Córdoba, Córdoba, Spain.
Endocrinology. 2012 Apr;153(4):1959-71. doi: 10.1210/en.2011-2032. Epub 2012 Feb 14.
Nesfatin-1, product of the precursor NEFA/nucleobindin2 (NUCB2), was initially identified as anorectic hypothalamic neuropeptide, acting in a leptin-independent manner. In addition to its central role in the control of energy homeostasis, evidence has mounted recently that nesfatin-1 is also produced in peripheral metabolic tissues, such as pancreas, adipose, and gut. Moreover, nesfatin-1 has been shown to participate in the control of body functions gated by whole-body energy homeostasis, including puberty onset. Yet, whether, as is the case for other metabolic neuropeptides, NUCB2/nesfatin-1 participates in the direct control of gonadal function remains unexplored. We document here for the first time the expression of NUCB2 mRNA in rat, mouse, and human testes, where NUCB2/nesfatin-1 protein was identified in interstitial mature Leydig cells. Yet in rats, NUCB2/nesfatin-1 became expressed in Sertoli cells upon Leydig cell elimination and was also detected in Leydig cell progenitors. Although NUCB2 mRNA levels did not overtly change in rat testis during pubertal maturation and after short-term fasting, NUCB2/nesfatin-1 content significantly increased along the puberty-to-adult transition and was markedly suppressed after fasting. In addition, testicular NUCB2/nesfatin-1 expression was up-regulated by pituitary LH, because hypophysectomy decreased, whereas human choriogonadotropin (super-agonist of LH receptors) replacement enhanced, NUCB2/nesfatin-1 mRNA and peptide levels. Finally, nesfatin-1 increased human choriogonadotropin-stimulated testosterone secretion by rat testicular explants ex vivo. Our data are the first to disclose the presence and functional role of NUCB2/nesfatin-1 in the testis, where its expression is regulated by developmental, metabolic, and hormonal cues as well as by Leydig cell-derived factors. Our observations expand the reproductive dimension of nesfatin-1, which may operate directly at the testicular level to link energy homeostasis, puberty onset, and gonadal function.
nesfatin-1 是前体 NEFA/核结合蛋白 2（NUCB2）的产物，最初被鉴定为作用于瘦素独立途径的下丘脑食欲肽。除了在能量稳态控制中的中枢作用外，最近有证据表明，nesfatin-1 也在胰腺、脂肪组织和肠道等外周代谢组织中产生。此外，nesfatin-1 已被证明参与控制全身能量稳态调节的身体功能，包括青春期启动。然而，像其他代谢神经肽一样，NUCB2/nesfatin-1 是否参与直接控制性腺功能仍未得到探索。我们首次在大鼠、小鼠和人睾丸中记录到 NUCB2 mRNA 的表达，在间质成熟的 Leydig 细胞中鉴定到 NUCB2/nesfatin-1 蛋白。然而，在大鼠中，Leydig 细胞消除后，NUCB2/nesfatin-1 在 Sertoli 细胞中表达，并在 Leydig 细胞祖细胞中检测到。尽管在青春期成熟和短期禁食期间，大鼠睾丸中 NUCB2 mRNA 水平没有明显变化，但 NUCB2/nesfatin-1 含量在青春期到成年期的过渡过程中显著增加，并在禁食后显著抑制。此外，睾丸 NUCB2/nesfatin-1 表达受垂体 LH 上调，因为垂体切除术降低，而人绒毛膜促性腺激素（LH 受体的超级激动剂）替代增强，NUCB2/nesfatin-1 mRNA 和肽水平。最后，nesfatin-1 增加了人绒毛膜促性腺激素刺激的离体大鼠睾丸组织的睾酮分泌。我们的数据首次揭示了 NUCB2/nesfatin-1 在睾丸中的存在和功能作用，其表达受发育、代谢和激素线索以及 Leydig 细胞衍生因子的调节。我们的观察结果扩展了 nesfatin-1 的生殖维度，它可能直接在睾丸水平上运作，将能量稳态、青春期启动和性腺功能联系起来。
