Irisin alleviates obesity-related spermatogenesis dysfunction via the regulation of the AMPKα signalling pathway

Abstract

Background Infertility is a common complication in obese men. Oxidative stress and testicular apoptosis play critical roles in obesity-induced spermatogenesis dysfunction. It has been reported that irisin, an exercise-induced myokine, may attenuate oxidative damage and testicular apoptosis in several diseases; however, its role in obesity-induced spermatogenesis dysfunction remains unclear. The purpose of this study was to investigate the role and underlying mechanism of irisin in obesity-induced dysfunction of spermatogenesis. Methods Male mice were fed a high-fat diet (HFD) for 24 weeks to establish a model of obesity-induced spermatogenesis dysfunction. To explore the effects of irisin, mice were subcutaneously infused with recombinant irisin for 8 weeks beginning at 16 weeks after starting a HFD. To confirm the role of AMP-activated protein kinase α (AMPKα), AMPKα-deficient mice were used. Results The data showed decreased serum irisin levels in obese patients, which was negatively correlated with sperm count and progressive motility. Irisin was downregulated in the plasma and testes of obese mice. Supplementation with irisin protected against HFD-induced spermatogenesis dysfunction and increased testosterone levels in mice. HFD-induced oxidative stress, endoplasmic reticulum (ER) stress and testicular apoptosis were largely attenuated by irisin treatment. Mechanistically, we identified that irisin activated the AMPKα signalling pathway. With AMPKα depletion, we found that the protective effects of irisin on spermatogenesis dysfunction were abolished in vivo and in vitro. Conclusions In conclusion, we found that irisin alleviated obesity-related spermatogenesis dysfunction via activation of the AMPKα signalling pathway. Based on these findings, we hypothesized that irisin is a potential therapeutic agent against obesity-related spermatogenesis dysfunction.

Effects of empagliflozin on the expression of kisspeptin gene and reproductive system function in streptozotocin-induced diabetic male rats

“…In fact, spermatozoa are more susceptible to oxidative stress due to the high levels of fatty acids in their plasma membranes. Previous studies have shown an increase in sperm membrane cholesterol and an increase in oxidative stress in obese individuals (3,4,6,7).…”

“…Diabetes mellitus is a metabolic disorder that is characterized by insulin resistance, hyperglycemia, dyslipidemia, and hypertension (1)(2)(3)(4). Oxidative stress, inflammation, and obesity which subsequently can lead to the production of oxidative stress and inflammation have a critical role in the development of diabetes (1)(2)(3)(4)(5)(6)(7).…”

“…(2015) was shown that obesity and inflammation, two key attributes in the development of diabetes, could impair the quality of sperm in male mice and decrease the amounts of testosterone in blood serum ( 2 ). These may be due to an increase in the cholesterol rate of the sperm membrane and an increase in oxidative stress in obese individuals ( 3 – 7 )…”

CRISPRa‐based activation of Fgf21 and Fndc5 ameliorates obesity by promoting adipocytes browning

“…Multiple analogues or mimetics of FGF21 have been developed to solve this problem, some of which have completed phase I clinical trials with a noticeable improvement in obesity and T2D‐related symptoms in patients 51,52 . The purification and biological characterization of recombinant human Irisin was performed by Panati in 2018 53 ; administration of recombinant Irisin also alleviates obesity and obesity‐related disorders in obese mice 54,55 . Besides the pharmacokinetic imperfections, recombinant myokines or analogues require periodic intake, which may be inconvenient and trigger immunoreaction due to the administration of exogenous proteins 5 .…”

Aerobic exercises regulate the epididymal anion homeostasis of high-fat diet-induced obese rats through TRPA1-mediated Cl− and HCO3− secretion

“…These findings suggest that obesity affects spermatogenesis in the testis and the subsequent sperm maturation in the epididymis. The effects of obesity and lack of physical exercises on spermatogenesis in the testis have been well documented over the past decades [12][13][14]. Martini et al analyzed the levels of A-glucosidase (NAG) in seminal plasma and proposed that the decrease of sperm motility in obese individuals is caused by the disorder of epididymal function [15].…”