Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility?

Abstract

Human feeding behavior and lifestyle are gradually being altered, favoring the development of metabolic diseases, particularly type 2 diabetes and obesity. Leptin is produced by the adipose tissue acting as a satiety signal. Its levels have been positively correlated with fat mass and hyperleptinemia has been proposed to negatively affect male reproductive function. Nevertheless, the molecular mechanisms by which this hormone affects male fertility remain unknown. Herein, we hypothesize that leptin acts on human Sertoli cells (hSCs), the "nurse cells" of spermatogenesis, altering their metabolism. To test our hypothesis, hSCs were cultured without or with leptin (5, 25 and 50ng/mL). Leptin receptor was identified by qPCR and Western blot. Protein levels of glucose transporters (GLUT1, GLUT2 and GLUT3), phosphofructokinase, lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by Western Blot. LDH activity was assessed and metabolite production/consumption determined by proton nuclear magnetic resonance. Oxidative damage was evaluated by assessing lipid peroxidation, protein carbonilation and nitration. Our data shows that leptin receptor is expressed in hSCs. The concentration of leptin found in lean, healthy patients, upregulated GLUT2 protein levels and concentrations of leptin found in lean and obese patients increased LDH activity. Of note, all leptin concentrations decreased hSCs acetate production illustrating a novel mechanism for this hormone action. Moreover, our data shows that leptin does not induce or protect hSCs from oxidative damage. We report that this hormone modulates the nutritional support of spermatogenesis, illustrating a novel mechanism that may be linked to obesity-induced male infertility.

Nutritional modifications in male infertility: a systematic review covering 2 decades

“…Studies showed that leptin can directly interact with its receptors on Leydig cells and regulates the synthesis of steroids within the testicles. 91,92 Leptin can modulate the firing rate of gonadotropins as well. 27 High amounts of leptin have been associated with impaired spermatogenesis and infertility, probably as a result of insufficient gonadotropin support, which leads to lower sperm quality.…”

Obesity, energy balance and spermatogenesis

“…At concentrations found in healthy lean men, leptin is able to upregulate the protein levels of GLUT2, whereas concentrations of leptin found in lean and obese patients increases the activity of LDH, the enzyme that catalyses the production of lactate necessary for the developing germ cells. Notably, all the concentrations of leptin decrease acetate production by Sertoli cells (Martins et al 2015), which could be associated with alteration in the cells lipid droplet accumulation. Accumulation of cytoplasmic lipid droplets, which has been associated with the elimination of germ cell-derived apoptotic bodies by phagocytosis (Wang et al 2006), was reported as one of the most striking deleterious effects of hyperthermia in Sertoli cells (Valles et al 2014).…”

The Burden of Metabolic Diseases on Male Reproductive Health

“…Therefore, a higher adipose tissue mass means higher leptin blood concentration, and obesity is associated to the highest values. GLUT expression is upregulated by leanlike leptin concentrations in Sertoli cells, but not by obese-like concentrations, although in both conditions acetate production was inhibited and LDH activity increased [21]. This data suggests a metabolic reroute towards β-oxidation using fatty acids as preferred substrate.…”