Paternal obesity induces metabolic and sperm disturbances in male offspring that are exacerbated by their exposure to an “obesogenic” diet

Abstract

Obesity and related comorbidities are becoming increasingly prevalent globally. In mice preconception paternal exposure to a high fat diet (HFD) impairs the metabolic and reproductive health of male offspring, despite their control diet (CD) consumption. However, offspring share lifestyle, including diet, with parents. We assessed if male offspring from HFD fathers have a heightened susceptibility to HFD-induced metabolic and reproductive derangements. This 2 × 2 design saw founder males (F0) and their offspring (F1) fed either a HFD or a nutritionally matched CD. Regardless of paternal diet, HFD fed male offspring had greater total body weight and adiposity. Offspring sired by a HFD male and fed a HFD were the heaviest, had the greatest adiposity and had the greatest concentration of serum cholesterol, triglyceride, HDL, and NEFA compared with CD sired/fed littermates. A synergistic increase in serum insulin was unmasked by both father/son HFD consumption, concomitant with increased sera glucose. Either a paternal or offspring HFD was associated with similar reductions to offspring sperm motility. Whereas sperm ROS concentrations and sperm–oocyte binding saw detrimental effects of both F0 HFD and F1 HFD with an interaction evident between both, culminating in the most impaired sperm parameters in this group. This indicates that metabolic and fertility disturbances in male offspring sired by HFD fathers are exacerbated by a “second-hit” of exposure to the same obesogenic environment postnatally. If translatable to human health, this suggests that adverse reproductive and metabolic outcomes may be amplified across generations through a shared calorie dense diet, relevant to the current worldwide obesity epidemic.

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

“…Most obese males have altered reproductive hormonal profiles, e.g. elevated estrogen and leptin levels, and decreased testosterone, follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), ghrelin and inhibin B levels (MacDonald et al 2010, McPherson & Lane 2015, Martins et al 2015, Cui et al 2017. In obese men, the hyperactivity of aromatase (cytochrome P450 enzyme) in redundant white adipose tissue causes excessive conversion of androgens into estrogens.…”

“…Recently, both clinical and experimental reveal the negative consequences of obesity on male reproductive function. According to the clinical investigation, men with overweight or obesity can decrease sperm quality including sperm concentration, sperm motility, acrosome reaction decline, increased sperm DNA damage and lower embryo implantation rates as well, comparing to those of normal BMI men (Jensen et al 2004, Dupont et al 2013, Samavat et al 2014, Shukla et al 2014, McPherson et al 2015, Soubry et al 2016. In consequence, obesity was associated with a more than 20% increased cases of subfertility and infertility (Cui et al 2016).…”

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

“…30 In addition, offspring fertility decreased after exposure of the father to a high fat diet. 31 Obesity is associated with pathophysiologic conditions and may have health impacts even on subsequent generations. We hypothesized that the fat content of a diet may have an impact on chromatin composition during gamete development and this may have the potential to influence the reprogramming process that takes place during the transition from spermatogonia to spermatids.…”

DOHaD et programmation pré- et péri-conceptionnelle

“…Chez les descendants de souris mâles soumis à un régime pauvre en protéines, le profil d'expression de nombreux gènes hépatiques, impliqués dans le métabolisme des lipides et du cholestérol, est altéré ; c'est le cas notamment de PPAR (peroxisome proliferator-activated receptor gamma) [32]. Toujours chez la souris, l'obésité paternelle induite par un régime hyperlipidique, altère chez les descendants les profils transcriptionnels testiculaire et spermatique -altération de microARN et diminution de méthylation globale de l'ADN [33,34]. Les descendants mâles et femelles adultes pré-sentent une intolérance au glucose, une résistance à l'insuline et une obésité [35].…”