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

Abstract

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

Caloric restriction alters the hormonal profile and testicular metabolome, resulting in alterations of sperm head morphology

“…Determination of mtDNA copy number. To study mtDNA copy number, we used a qPCR analysis in a CFX 96 thermocycler (Biorad, Hercules, CA), as described (40). Annealing temperatures and primer sequence are presented in Table 2.…”

Metabolic diseases affect male reproduction and induce signatures in gametes that may compromise the offspring health

“…Although the effects of GLP-1 in male reproduction remain overlooked, its contribution to glucose homeostasis suggests that it may be important for the regulation of spermatogenesis. The expression of the GLP-1 receptor was first identified in isolated human SCs by Martins et al ( 67 ). The authors also reported that exposure to GLP-1 decreased glucose consumption while increasing lactate production, in those cells.…”

“…The authors also reported that exposure to GLP-1 decreased glucose consumption while increasing lactate production, in those cells. Furthermore, GLP-1 modulates glucose metabolism of SCs and is suggested to have an anti-apoptotic effect in developing germ cells ( 67 ). In addition, it decreases T secretion ( 68 ), highlighting a possible effect in the hypothalamic–pituitary–gonadal (HPG) axis.…”

Molecular Mechanisms Controlled by mTOR in Male Reproductive System

“…In fact, subfertility or infertility associated with metabolic diseases has been linked with SC metabolic dysregulation. A recent study reported that treatment of human SCs with glucagon-like peptide-1 (GLP-1) increased p-mTOR levels at Ser244 [124]. GLP-1 analogues are used for the treatment of diabetes and obesity [125] promoting weight loss.…”