The Protective Effect of FGF21 on Diabetes-Induced Male Germ Cell Apoptosis Is Associated With Up-Regulated Testicular AKT and AMPK/Sirt1/PGC-1α Signaling
The Protective Effect of FGF21 on Diabetes-Induced Male Germ Cell Apoptosis Is Associated With Up-Regulated Testicular AKT and AMPK/Sirt1/PGC-1α Signaling
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DOI：
10.1210/en.2014-1619
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发表时间：
2015-03-01
期刊：
影响因子：
4.8
通讯作者：
Cai, Lu
中科院分区：
文献类型：
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作者：
Jiang, Xin;Chen, Jun;Cai, Lu
成纤维细胞生长因子21（FGF 21）是一种代谢调节因子，是正常精子发生所需的，并防止糖尿病诱导的生殖细胞凋亡。在这里，我们试图确定是否糖尿病诱导的生殖细胞凋亡，主要是由于增加氧化应激与受损的葡萄糖和脂肪酸代谢，通过检查FGF 21基因敲除（FGF 21-KO）或FGF 21治疗链脲佐菌素诱导的糖尿病小鼠的葡萄糖和脂肪酸代谢途径的影响。蛋白质印迹显示，蛋白激酶B（AKT）介导的葡萄糖信号在糖尿病睾丸中下调，并且在糖尿病发作后10天和2个月在FGF 21-KO糖尿病组中进一步降低，反映为糖原合成酶（GS）激酶（GSK）-3 β磷酸化减少和GS磷酸化增加。Fgf 21基因的缺失也使脂肪酸代谢相关因子、AMP活化蛋白激酶（AMPK）、沉默调节蛋白1（Sirt 1）和过氧化物酶体增殖物活化受体-γ共激活因子1 α（PGC-1 α）失活，沿着糖尿病诱导的睾丸氧化应激和损伤加重。重组FGF 21治疗部分预防了这些糖尿病效应。在FGF 21-KO非糖尿病小鼠中，睾丸AMPK/Sirt 1/PGC-1 α信号下调，AKT 1和小鼠双微体2沿着p53表达增加而失活，但AKT 2、GSK-3 β和GS未失活。这些结果表明，FGF 21在维持精子发生中的作用与其激活AKT 1和抑制p53有关。Fgf 21基因的缺失显著加剧了糖尿病诱导的睾丸AKT/GSK-3 β/GS和AMPK/Sirt 1/PGC-1 α通路的下调以及睾丸氧化应激和细胞凋亡。
Fibroblast growth factor 21 (FGF21) is a metabolic regulator that is required for normal spermatogenesis and protects against diabetes-induced germ cell apoptosis. Here, we tried to define whether diabetes-induced germ cell apoptosis that is predominantly due to increased oxidative stress was associated with impaired glucose and fatty acid metabolism, by examining the effects of Fgf21 gene knockout (FGF21-KO) or FGF21 treatment on the glucose and fatty acid metabolic pathways in streptozotocin-induced diabetic mice. Western blottings revealed that protein kinase B (AKT)-mediated glucose signaling was down-regulated in diabetic testes and further decreased in FGF21-KO diabetic group both 10 days and 2 months after diabetes onset, reflected by reduced glycogen synthase (GS) kinase (GSK)-3 beta phosphorylation and increased GS phosphorylation. Deletion of the Fgf21 gene also inactivated fatty acid metabolism-related factors, AMP-activated protein kinase (AMPK), sirtuin 1 (Sirt1), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha), along with exacerbating diabetes-induced testicular oxidative stress and damage. Treatment with recombinant FGF21 partially prevented these diabetic effects. In FGF21-KO nondiabetic mice, testicular AMPK/Sirt1/PGC-1 alpha signaling was down-regulated and AKT1 and murine double minute 2 were inactivated along with the increased p53 expression but not AKT2, GSK-3 beta, and GS. These results suggest that the role of FGF21 in maintaining spermatogenesis is associated with its activation of AKT1 and inhibition of p53. Deletion of the Fgf21gene significantly exacerbates diabetes-induced down-regulation of testicular AKT/GSK-3 beta/GS and AMPK/Sirt1/PGC-1 alpha pathways and testicular oxidative stress and cell apoptosis.