Diet-Induced Obesity in Male C57BL/6 Mice Decreases Fertility as a Consequence of Disrupted Blood-Testis Barrier

Abstract

Obesity is a complex metabolic disease that is a serious detriment to both children and adult health, which induces a variety of diseases, such as cardiovascular disease, type II diabetes, hypertension and cancer. Although adverse effects of obesity on female reproduction or oocyte development have been well recognized, its harmfulness to male fertility is still unclear because of reported conflicting results. The aim of this study was to determine whether diet-induced obesity impairs male fertility and furthermore to uncover its underlying mechanisms. Thus, male C57BL/6 mice fed a high-fat diet (HFD) for 10 weeks served as a model of diet-induced obesity. The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls. Besides, the sperm acrosome reaction fell accompanied by a decline in testosterone level and an increase in estradiol level in the HFD group. This alteration of sperm function parameters strongly indicated that the fertility of HFD mice was indeed impaired, which was also validated by a low pregnancy rate in their mated normal female. Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice. Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose. Taken together, obesity can impair male fertility through declines in the sperm function parameters, sex hormone level, whereas during spermatogenesis damage to the blood-testis barrier (BTB) integrity may be one of the crucial underlying factors accounting for this change.

Obesity, a serious etiologic factor for male subfertility in modern society

“…Actually, obese men are more likely to exhibit a reduction in semen quality than men with a normal weight and responsible to high risk of infertility. Consistently, abnormal sperm parameters including reduced sperm motility, decreased sperm counts and increased sperm deformity are also observed in the animal models with diet-induced obesity, thereby result in male subfertility , Fernandez et al 2011, Fan et al 2015. On the other hand, it was verified that many factors altered in obese male may impair sperm quality including sexual hormone imbalance, oxidative stress and chronic inflammation.…”

“…Similarly, declined sperm acrosome reaction induced by calcium ionophore A23187 is also observed in diet-induced obese mouse model (Fan et al 2015). Although the correlation between male obesity and sperm acrosome reaction is sparsely documented, it is reasonable that the impact of obesity on spermatogenesis and sperm maturation, which results in oxidative stress and membranous lipids alteration, may also cause some defects in acrosome reaction.…”

“…zonulin/zonula occludens-1 (ZO-1), occludin, claudins and actinmyosin cytoskeletal proteins, thereby induce opening of the cell junctions between the adjacent Sertoli cells and lead to disturbances in the niche of seminiferous epithelium essential for spermatogenesis (Zhang et al 2014, Chojnacka et al 2016, Li et al 2016, Stanton 2016. In fact, impaired BTB and decreased expression of junctional proteins in Sertoli cell have been observed in many obese animal models induced by diet (Liu et al 2014, Fan et al 2015.…”

“…Using difference gel electrophoresis or liquid chromatography tandem mass spectrometry (LC-MS), differential expressed proteins in spermatozoa from obese males are identified (Paasch et al 2011, Liu et al 2015. The low abundant proteins in obesity-associated asthenozoospermia are mainly associated with an array of biological functions including actin organization, flagellar assembly, vesicular traffic, protein degradation and stress resistance, and most of these proteins are involved in acrosome biogenesis, nuclear reshaping and flagellum formation during spermiogenesis that may directly causes abnormal sperm function.…”

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

“…We next questioned whether challenging male ΔCpt2 mice with a high-fat diet would result in more severe skeletal and metabolic phenotypes, since high-fat diet feeding and the ensuing accumulation of adipose tissue increases estrogen levels in males ( Figure 5A) (44,45). Cohorts of 4-week-old male control and ΔCpt2 mice were fed a high-fat diet (60% of calories from fat) for 8 weeks before analysis.…”