Emerging Role for Mammalian Target of Rapamycin in Male Fertility

Oliveira, Pedro F.; Cheng, C. Yan; Alves, Marco G.

doi:10.1016/j.tem.2016.12.004

Cited by 35 publications

(27 citation statements)

References 16 publications

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“…According to a recent study that supports our results, increased activity of mTORC1 due to decreased liver kinase B1 leads to an increase in Sertoli cell (SC) proliferation, with notable deficiencies in SC polarity and localisation of junctional complexes in young mice (Oliveira et al, ). Moreover, our findings were supported by the hypothesis of Hobbs et al, who stated that a subset of spermatogonia may vary in their response to increased mTORC1 and may lead to impaired spermatogenesis (Hobbs et al, ).…”

Section: Discussionsupporting

confidence: 87%

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The correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele

et al. 2019

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This study aimed to assess the possible correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele. The study included sixty infertile males and fifty fertile males as controls. The infertile group was subdivided into the following subgroups: thirty males with varicocele and thirty males without varicocele. All subjects underwent medical history collection, clinical examination, semen analysis, sperm DNA integrity assessment, mTOR gene expression assessment and scrotal colour Doppler ultrasound. The mean mTOR gene expression in infertile patients with varicocele (23.52 ± 14.65) was significantly higher than that in infertile patients without varicocele (12.24 ± 12.44) and fertile control subjects (3.92 ± 3.26; p = 0.003 and p < 0.001 respectively). In the infertile varicocele‐positive group, mTOR gene expression showed a significant negative correlation with sperm count (p = 0.028, r = −0.400) and progressive sperm motility (p = 0.038, r = −0.381), as well as a significant positive correlation with the sperm DNA fragmentation index (DFI; p = 0.001, r = 0.578). In the infertile varicocele‐negative group, mTOR gene expression showed a significant negative correlation with progressive sperm motility (p = 0.018, r = −0.429) and a significant positive correlation with sperm DFI (p < 0.001, r = 0.673). In conclusion, according to these results, there is a significant positive correlation between mTOR gene expression and sperm DFI among infertile patients with and without varicocele.

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Section: Discussionsupporting

confidence: 87%

“…This finding suggests that mTORC1 has a role in spermatogenesis. Moreover, both mTOR complexes are involved in the regulation of blood testicular barrier dynamics during spermatogenesis (Oliveira, Cheng, & Alves, ; Xu et al, ).…”

Section: Introductionmentioning

confidence: 99%

The correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele

et al. 2019

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“…Indeed, in other cellular systems, such as intestinal epithelial cells (Fazolini et al 2015), leptin activates the mTOR pathway triggering lipid droplet formation. mTOR controls Sertoli cells redox balance and metabolism (Jesus et al 2016) and has been discussed as a central rheostat regulator of male reproductive potential (Jesus et al 2017, Oliveira et al 2017. Thus, it may be a key player in obesity-induced male subfertility/infertility by controlling lipid droplet formation in testicular cells, among other mechanisms.…”

Section: Energy Balance Hormonal Dysfunction and Male Reproductionmentioning

confidence: 99%

Obesity, energy balance and spermatogenesis

Oliveira¹,

Sousa²,

Silva³

et al. 2017

Reproduction

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Obesity has grown to pandemic proportions. It affects an increasing number of children, adolescents and young adults exposed to the silent comorbidities of this disorder for a longer period. Infertility has arisen as one important comorbidity associated with the energy dysfunction promoted by obesity. Spermatogenesis is a highly regulated process that is determined by specific energetic requirements. The reproductive potential of males relies on hormonal-dependent and -independent stimuli that control sperm quality. There are conflicting data concerning the impact of male overweight and obesity on sperm quality, as well as on the possible paternal-induced epigenetic trait inheritance of obesity. In addition, it remains a matter of debate whether massive weight loss induced by lifestyle interventions, drugs or bariatric surgery may or may not benefit obese men seeking fatherhood. Herein, we propose to discuss how energy balance may modulate hormonal signalling and sperm quality in overweight and obese men. We also discuss some molecular mechanisms that mediate obesity-related dysfunction in male reproductive system and how paternal obesity may lead to trait inheritance. Finally, we will discuss how lifestyle modifications and sustained weight loss, particularly the loss achieved by bariatric surgery, may revert some of the deleterious effects of obesity in men and their offspring.Reproduction (2017) 153 R173-R185

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“…These metabolic processes depend on signalling pathways network. The mammalian target of rapamycin (mTOR) kinase emerged as pivotal for these processes (for review Oliveira et al, 2017), controlling mitochondrial bioenergetics and glucose metabolism. GLP-1 interferes with mTOR pathway (Park et al, 2015) and recently it was suggested that mTOR has an essential role in male reproduction (Jesus et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Metabolic dynamics of human Sertoli cells are differentially modulated by physiological and pharmacological concentrations of GLP-1

Martins

Monteiro

Silva

et al. 2019

Toxicology and Applied Pharmacology

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Obesity incidence has pandemic proportions and is expected to increase even further. Glucagon-like peptide-1 (GLP-1) based therapies are well-established pharmacological resources for obesity treatment. GLP-1 regulates energy and glucose homeostasis, which are also crucial for spermatogenesis. Herein, we studied the GLP-1 effects in human Sertoli cells (hSCs) metabolism and mitochondrial function. hSCs were cultured in absence or exposed to increasing doses of GLP-1 mimicking physiological post-prandial (0.01 nM) levels or equivalent to pharmacological levels (1 and 100 nM) used for obesity treatment. We identified GLP-1 receptor in hSCs. Consumption/ production of extracellular metabolites were assessed, as well as protein levels or activities of glycolysis-related enzymes and transporters. Mitochondrial membrane potential and oxidative damage were evaluated. Glucose consumption decreased, while lactate production increased in hSCs exposed to 0.01 and 1 nM GLP-1. Though lactate dehydrogenase (LDH) protein decreased after exposure to 100 nM GLP-1 its activity increased in hSCs exposed to the same concentration of GLP-1. Mitochondrial membrane potential decreased in hSCs exposed to 100 nM of GLP-1, while formation of carbonyl groups was decreased in those cells. Those effects were followed by an increase in p-mammalian target of rapamycin (mTOR) Ser(2448). Overall, the lowest concentrations of GLP-1 increased the efficiency of glucose conversion to lactate, while GLP-1 concentration of 100 nM induces mTOR phosphorylation, decreases mitochondrial membrane potential and oxidative damage. GLP-1 regulates testicular energy homeostasis and pharmacological use of GLP-1 analogues could be valuable to counteract the negative impact of obesity in male reproductive function. et al., 2016). Dysregulation in the hormonal control of energy homeostasis promoted by the balance between food intake and energy expenditure has been hypothesized to interfere not only in body metabolism, but also with fertility though the underlying mechanisms remain unknown. Glucagon like peptide-1 (GLP-1) is a 29-amino acid amidated

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Emerging Role for Mammalian Target of Rapamycin in Male Fertility

Cited by 35 publications

References 16 publications

The correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele

The correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele

Obesity, energy balance and spermatogenesis

Metabolic dynamics of human Sertoli cells are differentially modulated by physiological and pharmacological concentrations of GLP-1

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