Exogenous leptin affects sperm parameters and impairs blood testis barrier integrity in adult male mice

Abstract

BackgroundSerum leptin levels are augmented in obese infertile men and in men with azoospermia. They also correlate inversely with sperm concentration, motility and normal forms. The mechanisms underlying the adverse effects of excess leptin on male reproductive function remain unclear. The present study aimed to evaluate the effects of exogenous leptin on sperm parameters in mice and to explore the underlying mechanisms.MethodsWe treated normal adult male mice with saline, 0.1, 0.5 or 3 mg/kg leptin daily for 2 weeks. After treatment, serum leptin levels, serum testosterone levels, sperm parameters and testicular cell apoptosis were evaluated. Blood testis barrier integrity and the expression of tight junction-associated proteins in testes were also assessed. We further verified the direct effects of leptin on tight junction-associated proteins in Sertoli cells and the possible leptin signaling pathways involved in this process.ResultsAfter treatment, there were no significant differences in body weights, reproductive organ weights, serum leptin levels and serum testosterone levels between leptin-treated mice and control mice. Administration of 3 mg/kg leptin reduced sperm concentration, motility and progressive motility while increasing the percentage of abnormal sperm and testicular cell apoptosis. Mice treated with 3 mg/kg leptin also had impaired blood testis barrier integrity, which was related to decreased tight junction-associated proteins in testes. Leptin directly reduced tight junction-associated proteins in Sertoli cells, JAK2/STAT, PI3K and ERK pathways were suggested to be involved in this process.ConclusionsExogenous leptin negatively affects sperm parameters and impairs blood testis barrier integrity in mice. Leptin reduced tight junction-associated proteins in Sertoli cells, indicating that leptin has a direct role in impairing blood testis barrier integrity. Given the function of blood testis barrier in maintaining normal spermatogenesis, leptin-induced blood testis barrier impairment may be one of the mechanisms contributing to male subfertility and infertility.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0368-4) contains supplementary material, which is available to authorized users.

Leptin and reproductive dysfunction in obese men

“…Studies on Sprague‐Dawley rats treated with 60 μg/kg body weight of leptin for either 6 or 2 weeks also came to the same conclusions (Almabhouh et al, ; Md Mokhtar et al, ). Similar response was also noted in mice recently when given exogenous leptin, although the doses ranging from 0.5 to 3.0 mg/Kg body used in this study were much higher than those used in Sprague‐Dawley rats (Wang, Zhang, Hu, & Li, ). While the precise mechanism responsible for these leptin‐induced effects on spermatozoa and seminiferous tubules remains uncertain, leptin‐induced increase in free radical production (ROS) is however implicated (Abbasihormozi et al, ).…”

“…In general, it appears that oxidative stress following leptin treatment is responsible for the increased apoptosis of spermatozoa and seminiferous tubular cells, which might then be responsible for the decreased sperm concentration (Almabhouh et al, ; Wang et al, ). In fact, this might have also contributed to the leptin‐induced decreases in height and diameter of seminiferous tubules and sperm count reported recently in Sprague‐Dawley (Haron et al, ; Md Mokhtar et al, ).…”

“…Apart from increasing oxidative stress, leptin might also impact the blood–testis barrier. Administration of leptin at a dose of 3 mg/kg for 2 weeks to adult, male mice resulted in testicular cell apoptosis, decreased claudin 5, occludin and ZO‐1 expression and impaired blood–testis barrier integrity (Wang et al, ). The blood–testis barrier acts as both physical and immunological barrier that protect the germ cells from the body's immune system and from other circulating toxicants (Cheng & Mruk, ).…”

Orlistat attenuates obesity‐induced decline in steroidogenesis and spermatogenesis by up‐regulating steroidogenic genes

“…Studies have demonstrated that the absence of endogenous leptin is associated with hypogonadism, 53,54 yet, high leptin level is reported to suppress steroidogenesis 54 . Human and experimental studies have linked significant decline in testosterone level, impairment in sperm count and motility, and increases in sperm abnormal morphology and DNA fragmentation, with high leptin levels 55‐57 . In fact, experiments demonstrated that exogenous leptin administration impacted negatively on sperm parameters in rats, 58,59 thus raising concerns about leptin levels in subfertile/infertile obese men.…”

Association between leptin, obesity, hormonal interplay and male infertility

“…It also has a direct local effect on leydig and sertoli cell function (Lampiao, Agarwal, & du Plessis, ). Serum leptin levels have been found to be high in most obese people and rodents with high‐fat diet ingestion for a long term (Wang, Zhang, Hu, & Li, ).…”