除了与2型糖尿病等代谢问题的联系,比如生活方式,环境,超重也可能影响生育能力。成纤维细胞生长因子21(FGF21),一种与能量平衡相关的肝脏来源的激素,最近成为雌性哺乳动物繁殖的潜在参与者。在男性中,只有两项研究描述了FGF21对生育能力的潜在影响.最近的一项研究描述了在呈现低睾酮水平与升高的FGF21血浆水平相关的肥胖患者中观察到的负相关。探讨FGF21在类固醇生成中的作用,我们已经研究了FGF21参与Leydig细胞的脂质和类固醇活性。如通过RT-qPCR和通过蛋白质印迹确定的,Leydig细胞模型表达所有FGF21受体和β-Klotho辅因子。培养的mLTC-1Leydig细胞系暴露于增加的FGF21浓度诱导的Akt磷酸化(Ser473)并修饰了CREB因子活性,提示FGF21通路的功能。FGF21对mLTC-1Leydig细胞的影响是抑制脂质合成,导致脂滴含量的减少。脂质合成的下降与脂质含量的减少有关(主要是PUFA,胆固醇酯化,和甘油三酯)通过脂质组学方法测量。主要结果是减少胆固醇的数量,类固醇的前体,在mLTC-1Leydig细胞中,并与睾丸激素的低产生有关。雄激素的减少也与类固醇酶基因表达的减少有关,在CREB活动的控制下,并且由于低cAMP细胞内水平而呈现较低的活性。在体内,在成年雄性小鼠中施用FGF21后,类固醇的产生降低,这与精子的进行性运动和速度降低有关。此外,这些实验数据通过数据挖掘分析得到加强,重点是1,319,905篇参考文献中的“性腺”术语,显示了已经描述的FGF21与脂肪酸途径之间的联系,胆固醇储存,和类固醇生产。总之,我们证明睾丸中的Leydig细胞存在功能性FGF21通路,调节脂质代谢和类固醇功能。在mLTC-1睾丸间质细胞中,FGF21降低胆固醇,PUFA含量,和睾丸激素的生产。最后,这项工作强调了肝细胞因子FGF21可能对雄激素合成和睾丸活性产生负面影响。
Beyond their link to metabolic issues like type 2 diabetes, factors like lifestyle, environment, and excess weight may also influence fertility. Fibroblast growth factor 21 (FGF21), a liver-derived hormone linked to energy balance, has recently emerged as a potential player in female mammalian reproduction. In male, only two studies have described potential effects of FGF21 on fertility. A recent study has described a negative correlation observed in obese patients presenting a low testosterone level associated with elevated FGF21 plasma levels. To investigate the role of FGF21 in steroidogenesis, we have studied the involvement of FGF21 in lipid and steroid activity by Leydig cells. Leydig cell model expressed all FGF21 receptors and β-Klotho cofactor as determined by RT-qPCR and by western-blot. Cultured mLTC-1 Leydig cell line exposed to increasing FGF21 concentration induced phosphorylation (Ser 473) of Akt and modified the CREB factor activity, suggesting the functionality of the FGF21 pathway. FGF21 consequences on mLTC-1 Leydig cells are inhibition of the lipid synthesis, leading to a reduction in the content of lipid droplets. The drop in lipid synthesis is associated with a reduction in the amount of lipids (mainly PUFA, cholesterol esterified, and triglycerides) as measured by
lipidomic approach. The main consequence is to reduce the quantity of cholesterol, the steroid precursor, in mLTC-1 Leydig cells and is associated with a low production in testosterone. The decrease in androgens was also associated with a reduction in the steroid enzyme genes expression, which are under the control of CREB activity, and present a lower activity due to low cAMP intracellular levels. In vivo, steroid production was lowering after FGF21 administration in adult male mice associated to a decrease in progressive motility and velocity of sperm. In addition, these experimental data are reinforced by a data mining analysis focused on \"gonad\" terms in 1,319,905 article references showing the link already described between FGF21 with the fatty acids pathways, cholesterol storage, and steroid production. In conclusion, we demonstrated that Leydig cells in the testes present a functional FGF21 pathway, which regulates lipid metabolism and steroid function. In mLTC-1 Leydig cells, FGF21 reduced cholesterol, PUFA content, and testosterone production. Finally, this work highlighted that the hepatokine FGF21 could have a negative impact on androgen synthesis and testicular activity.