背景:男性精液体积的减少与全球肥胖患病率的上升相当。合成代谢激素胰岛素样生长因子-1(IGF-1)可促进培养小鼠精原干细胞的增殖和分化,减轻体外精子发生异常。此外,血清IGF-1水平与体重指数呈负相关。而IGF-1在肥胖男性精子产生中的作用尚不清楚。
目的:探讨IGF-1对高脂饮食(HFD)诱导的肥胖小鼠精子发生的治疗作用及其机制。
方法:建立HFD诱导的肥胖小鼠模型。睾丸形态改变,精子计数,扩散,H&E染色观察细胞凋亡,免疫组织化学,免疫荧光,和西方印迹。向肥胖小鼠施用外源性重组IGF-1以研究睾丸IGF-1水平改变与精子产生之间的相关性。
结果:精子数量减少,睾丸结构紊乱,与正常饮食喂养的小鼠相比,HFD喂养的小鼠的性激素水平异常。增殖相关抗原如增殖细胞核抗原(PCNA)和Ki-67的表达降低,而HFD喂养小鼠睾丸中c-caspase3等促凋亡蛋白的含量增加。最重要的是,由于肝细胞和支持细胞中IGF-1的减少,睾丸中胰岛素样生长因子-1受体(IGF-1R)的磷酸化降低.重组IGF-1通过促进IGF-1R减轻这些功能损伤,Akt,和Erk1/2在睾丸中的磷酸化。
结论:IGF-1/IGF-1R信号传导不足与肥胖雄性小鼠精子生成受损密切相关。外源性IGF-1可以改善存活和增殖以及精子产生。本研究为肥胖男性少精子症的治疗提供了新的理论依据和靶点。
BACKGROUND: A decrease in semen volume among men is comparable to the rising prevalence of obesity worldwide. The anabolic hormone insulin-like growth factor-1 (IGF-1) can promote proliferation and differentiation in cultured mouse spermatogonial stem cells and alleviate abnormal in vitro spermatogenesis. Additionally, serum IGF-1 level is negatively correlated with body mass index. Whereas the role of IGF-1 in the sperm production in obese men remains unclear.
OBJECTIVE: To investigate the therapeutic effect and potential mechanism of IGF-1 on spermatogenesis of high-fat diet (HFD)-induced obesity mice.
METHODS: An HFD-induced obesity mouse model was established. Alterations in testicular morphology, sperm count, proliferation, and apoptosis were observed by H&E staining,immunohistochemistry, immunofluorescence, and Western blotting. Exogenous recombinant IGF-1 was administered to obese mice to investigate the correlations between altered testicular IGF-1 levels and sperm production.
RESULTS: The sperm count was reduced, the testicular structure was disordered, and sex hormone levels were abnormal in HFD-fed mice compared with normal diet-fed mice. The expression of proliferation-related antigens such as proliferating cell nuclear antigen (PCNA) and Ki-67 was decreased, while that of proapoptotic proteins such as c-caspase3 was increased in testes from HFD-fed mice. Most importantly, the phosphorylation of insulin-like growth factor-1 receptor (IGF-1R) in testes was decreased due to reductions in IGF-1 from hepatocytes and Sertoli cells. Recombinant IGF-1 alleviated these functional impairments by promoting IGF-1R, Akt, and Erk1/2 phosphorylation in the testes.
CONCLUSIONS: Insufficient IGF-1/IGF-1R signaling is intimately linked to damaged sperm production in obese male mice. Exogenous IGF-1 can improve survival and proliferation as well as sperm production. This study provides a novel theoretical basis and a target for the treatment of obese men with oligozoospermia.