Metformin Improves Fertility in Obese Males by Alleviating Oxidative Stress-Induced Blood-Testis Barrier Damage.

Jifeng Ye,Zhenhua Tian,Chunxiao Yu,Dandan Luo,Meijie Zhang,Xiaohui Su,Xiaolin Xu,Qingbo Guan,Mingqi Sun

doi:10.1155/2019/9151067

Abstract

Background/Aims Obesity, which is related to increased oxidative stress in various tissues, is a risk factor for male infertility. Metformin is reported to have an antioxidant effect; however, the precise role of metformin in obesity-induced male infertility remains unknown. The current study is aimed at exploring the effects of metformin and characterizing its underlying mechanism in the fertility of obese males. Methods An obese male mouse model was generated by feeding mice with a high-fat diet; then, the mice were administered metformin in water for 8 weeks. Reproductive ability, metabolic parameters, and follicle-stimulating hormone (FSH) were assessed by cohabitation, enzymatic methods, and ELISA, respectively. Damage to the integrity of the blood-testis barrier (BTB), which ensures spermatogenesis, was assessed by transmission electron microscopy and immunofluorescence with a biotin tracer. Malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were employed for the assessments of oxidative stress. BTB-related proteins were measured by immunoblotting. Nuclear factor κB (NF-κB) was assessed by immunofluorescence. Results High-fat-diet-fed mice presented evident lipid metabolic disturbances, disrupted BTB integrity, and decreased reproductive function. Metformin alleviated the decrease in male fertility, decreased ectopic lipid deposition in the testis, and increased serum FSH levels. A further mechanistic analysis revealed that metformin ameliorated the high-fat-diet-induced injury to the BTB structure and permeability and restored the disordered BTB-related proteins, which might be associated with an improvement in oxidative stress and a recovery of NF-κB activity in Sertoli cells (SCs). Conclusion Metformin improves obese male fertility by alleviating oxidative stress-induced BTB damage. These findings provide new insights into the effect of metformin on various diseases and suggest future possibilities in the treatment of male infertility.

Highlights

Obesity is a complex metabolic disease that is determined by lifestyle factors, including environmental and genetic factors
Accompanied by weight gain, there was a significant increase of epididymal adipose in high-fat-diet mice (0 24 ± 0 10 vs. 1 37 ± 0 13, P < 0 01, Figure 1(d)), there was no change in testicular weight (Figure 1(c))
These findings demonstrated that an obese mouse model induced with a high-fat diet was successfully established

Summary

Introduction

Obesity is a complex metabolic disease that is determined by lifestyle factors, including environmental (food variety and intake, physical activity) and genetic factors. Obesity has become a predominant health problem and has increased globally at an alarming rate [1]. Obesity increases the risk for hypertension, diabetes, cardiovascular disease, and some cancers [2,3,4,5,6]. Overweight men or men with obesity show a decline in sperm quality, an increase in sperm DNA damage, and a decrease in embryo implantation rates compared with men with. Animal experiments have shown that a high-fat diet can increase the male infertility rate and decrease sperm parameters [11,12,13]. Many previous studies involving mechanistic explorations have mainly focused on the effects of obesity or a high-fat diet on germ cells or Leydig cells. Whether and how obesity damages Sertoli cells (SCs) or the blood-testis barrier (BTB) remains unclear

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Discussion

Conclusion