Metformin Ameliorates Testicular Function and Spermatogenesis in Male Mice with High-Fat and High-Cholesterol Diet-Induced Obesity

Abstract

The aim of this study was to investigate the effects of metformin supplementation on metabolic dysfunction, testicular antioxidant capacity, apoptosis, inflammation and spermatogenesis in male mice with high-fat and high-cholesterol diet-induced obesity. Forty male C57BL/6 mice were fed a normal diet (NC group, n = 10) or a high-fat and high-cholesterol diet (HFC group, n = 30) for 24 weeks, and mice randomly chosen from the HFC group were later treated with metformin for the final 8 weeks of HFC feeding (HFC + Met group, n = 15). Compared with the HFC group, the obese mice supplemented with metformin exhibited improved blood cholesterol, glucose and insulin resistance. The HFC group diminishes in the sperm motility and normal sperm morphology, while the poorer maturity of testicular spermatogenesis was improved by metformin treatment. The HFC group exhibited a higher estradiol level and a lower 17β-HSD protein expression. Further analyses showed that metformin treatment increased the activities of superoxide dismutase, catalase and glutathione peroxidase and reduced lipid peroxidation. Nevertheless, both the HFC and HFC + Met groups exhibited increased expressions of apoptosis and inflammation proteins in the testis. Metformin treatment ameliorated obesity-induced poor testicular spermatogenesis and semen quality through increasing the testosterone level and antioxidant capacity.

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…Since MF improves the lipid and carbohydrate metabolism, increases insulin sensitivity, prevents overproduction of reactive oxygen species and pro-inflammatory factors in men with MetS and T2DM, the use of MF therapy should thereby have a restorative effect on reproductive functions in men with these metabolic disorders [ 94 , 429 ]. Indeed, there are the experimental and clinical evidences of a positive effect of MF on the male reproductive dysfunctions in MetS and T2DM, but the mechanisms and the factors influencing the effectiveness of the restorative MF action are still poorly understood [ 94 , 430 , 431 ]. In addition, a number of authors did not confirm the improving effect of MF on male reproduction or even showed its negative effect on androgenic status in men with severe obesity and T2DM [ 432 , 433 , 434 ].…”

“…The key role in the development of testicular dysfunctions and in the deterioration of spermatogenesis and steroidogenesis belongs to the activation of oxidative stress, inflammation and apoptosis in the testes. Since MF has pronounced anti-inflammatory, antioxidant and antiapoptotic effects on testicular cells, these effects may be largely due to the MF-induced restoration of spermatogenesis and steroidogenesis in experimental MetS and DM [ 431 , 450 , 452 , 453 , 454 , 457 ]. The treatment of male Sprague-Dawley rats with MetS using MF (100 mg/kg/day, 8 weeks) weakens the apoptotic and pro-inflammatory processes in the testes and, thereby, increases the number of spermatogonia, Sertoli and Leydig cells and motile spermatozoa, decreases the number of small, atrophic and distorted seminiferous tubules, and improves the morphology of the seminiferous tubules [ 450 ].…”

“…The antioxidant effect of MF was critical for its restorative effect on spermatogenesis and steroidogenesis in C57BL/6 mice with MetS induced by a HFD and cholesterol-rich diet [ 431 ]. A high content of cholesterol in food led to an increase in intratesticular cholesterol concentration, provoked the deposition of lipids in the seminiferous tubules, and impaired the morphology of the Leydig cells, stimulating the ER stress and apoptosis, culminating in reduction of testosterone synthesis [ 458 , 459 ].…”

“…Eight-week administration of MF led to a decrease in atherogenic cholesterol levels in the blood and lowered the cholesterol level in the testes, restoring intratesticular testosterone levels, which were decreased in MetS. Along with this, in MF-treated mice, the expression of 17β-HSD was restored [ 431 ]. The 17β-HSD catalyzes the final stage of testicular steroidogenesis, the conversion of androstenedione to testosterone.…”

Metabolic Syndrome and Reproduction

“…Several studies on animal models reported that metformin ameliorates testicular function and sperm quality in male mice [ 100 , 101 ] and rats [ 102 , 103 , 104 ] exposed to an obesogenic (high-fat [ 89 , 105 ] or high-sugar [ 102 ]) diet, as well as in streptozotocin-induced diabetic rats [ 106 , 107 , 108 ]. Conversely, some authors [ 109 ] reported a negative effect of metformin in Sertoli cell proliferation and daily sperm production in rats.…”