Barreiro M L, Gaytan F, Castellano J M, Suominen J S, Roa J, Gaytan M, Aguilar E, Dieguez C, Toppari J, Tena-Sempere M
Physiology Section, Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of Cordoba, Avda. Menéndez Pidal s/n, 14004 Cordoba, Spain.
Endocrinology. 2004 Nov;145(11):4825-34. doi: 10.1210/en.2004-0732. Epub 2004 Jul 29.
Ghrelin has emerged as putative regulator of an array of endocrine and nonendocrine functions, including cell proliferation. Recently, we provided evidence for the expression of ghrelin in mature, but not in undifferentiated, Leydig cells of rat and human testis. Yet testicular actions of ghrelin, other than modulation of testosterone secretion, remain unexplored. In the present study we evaluated the effects of ghrelin on proliferation of Leydig cell precursors during puberty and after selective elimination of mature Leydig cells by treatment with ethylene dimethane sulfonate. In these settings, intratesticular injection of ghrelin significantly decreased the proliferative activity of differentiating immature Leydig cells, estimated by 5-bromodeoxyuridine labeling. This response was selective and associated, in ethylene dimethane sulfonate-treated animals, with a decrease in the mRNA levels of stem cell factor (SCF), i.e. a key signal in spermatogenesis and a putative regulator of Leydig cell development. Thus, the effects of ghrelin on SCF gene expression were evaluated. In adult rats, ghrelin induced a significant decrease in SCF mRNA levels in vivo. Such an inhibitory action was also detected in vitro using cultures of staged seminiferous tubules. The inhibitory effect of ghrelin in vivo was dependent on proper FSH input, because it was detected in hypophysectomized rats only after FSH replacement. Overall, it is proposed that acquisition of ghrelin expression by Leydig cell precursors during differentiation may operate as a self-regulatory signal for the inhibition of the proliferative activity of this cell type through direct or indirect (i.e. SCF-mediated) mechanisms. In addition, we present novel evidence for the ability of ghrelin to modulate the expression of the SCF gene, which may have implications for the mode of action of this molecule in the testis as well as in other physiological systems.
胃饥饿素已成为一系列内分泌和非内分泌功能（包括细胞增殖）的假定调节因子。最近，我们提供证据表明，胃饥饿素在大鼠和人类睾丸的成熟间质细胞中表达，但在未分化的间质细胞中不表达。然而，除了调节睾酮分泌外，胃饥饿素在睾丸中的作用仍未得到探索。在本研究中，我们评估了胃饥饿素对青春期期间以及用乙烷二甲磺酸盐处理选择性消除成熟间质细胞后间质细胞前体增殖的影响。在这些情况下，通过5-溴脱氧尿苷标记估计，睾丸内注射胃饥饿素显著降低了分化中的未成熟间质细胞的增殖活性。在乙烷二甲磺酸盐处理的动物中，这种反应具有选择性，并且与干细胞因子（SCF）的mRNA水平降低有关，SCF是精子发生中的关键信号和间质细胞发育的假定调节因子。因此，评估了胃饥饿素对SCF基因表达的影响。在成年大鼠中，胃饥饿素在体内诱导SCF mRNA水平显著降低。在体外使用分期生精小管培养物也检测到了这种抑制作用。胃饥饿素在体内的抑制作用依赖于适当的促卵泡激素输入，因为仅在促卵泡激素替代后在垂体切除的大鼠中才检测到这种作用。总体而言，有人提出，间质细胞前体在分化过程中获得胃饥饿素表达可能通过直接或间接（即SCF介导）机制作为一种自我调节信号来抑制这种细胞类型的增殖活性。此外，我们提供了新的证据表明胃饥饿素能够调节SCF基因的表达，这可能对该分子在睾丸以及其他生理系统中的作用方式具有影响。
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