Effect of Metformin on Sertoli Cell Fatty Acid Metabolism and Blood-Testis Barrier Formation.

Sertoli cells (SCs) are essential to maintaining germ cell development. Metformin, the main pharmacologic treatment for pediatric type 2 diabetes, is administered to children during SC maturation. The present study aimed to analyze whether metformin affects SC energy metabolism and blood-testis barrier (BTB) integrity. Primary SC cultures were used for the in vitro studies. In vivo effects were studied in Sprague-Dawley rats treated with 200 mg/kg metformin from Pnd14 to Pnd30. Metformin decreased fatty acid oxidation and increased 3-hydroxybutyrate production in vitro. Moreover, it decreased the transepithelial electrical resistance across the monolayer and induced ZO-1 redistribution, suggesting an alteration of cell junctions. In vivo, a mild but significant increase in BTB permeability and ZO-1 expression was observed in the metformin group, without changes in testicular histology and meiosis progression. Additionally, adult rats that received metformin treatment during the juvenile period showed no alteration in BTB permeability or daily sperm production. In conclusion, metformin exposure may affect BTB permeability in juvenile rats, but this seems not to influence spermatogenesis progression. Considering the results obtained in adult animals, it is possible to speculate that metformin treatment during the juvenile period does not affect testicular function in adulthood.

Glycolysis as key regulatory step in FSH-induced rat Sertoli cell proliferation: Role of the mTORC1 pathway.

The definitive number of Sertoli cells (SCs), achieved during the proliferative periods, defines the spermatogenic capacity in adulthood. It is recognized that FSH is the main mitogen targeting SC and that it exerts its action, at least partly, through the activation of the PI3K/Akt/mTORC1 pathway. mTORC1 controls a large number of cellular functions, including glycolysis and cell proliferation. Interestingly, recent evidence revealed that the glycolytic flux might modulate mTORC1 activity and, consequently, cell cycle progression. Although mature SC metabolism has been thoroughly studied, several aspects of metabolism regulation in proliferating SC are still to be elucidated. The objective of this study was to explore whether aerobic glycolysis is regulated by FSH through mTORC1 pathway in proliferating SC, and to assess the involvement of glycolysis in the regulation of SC proliferation. The present study was carried out utilizing 8-day-old rat SC cultures. The results obtained show that FSH enhances glycolytic flux through the induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and lactate dehydrogenase A (LDHA) in an mTORC1 dependent manner. In addition, PFKFB3 and LDH inhibitors prevent FSH from activating mTORC1 and stimulating SC proliferation and glycolysis, presumably through mTORC1 pathway inhibition. In summary, FSH simultaneously regulates SC proliferation and glycolysis in an mTORC1 dependent manner, and glycolysis seems to cooperate with FSH in the stimulation of both cellular functions through the modulation of the same signalling pathway. Therefore, a positive feedback between the mTORC1 pathway and glycolysis triggered by FSH is hypothesized.

Cardiac changes in apoptosis, inflammation, oxidative stress, and nitric oxide system induced by prenatal and postnatal zinc deficiency in male and female rats.

PURPOSE: Zinc restriction during fetal and postnatal development could program cardiovascular diseases in adulthood. The aim of this study was to determine the effects of zinc restriction during fetal life, lactation, and/or post-weaning growth on cardiac inflammation, apoptosis, oxidative stress, and nitric oxide system of male and female adult rats. METHODS: Wistar rats were fed a low- or a control zinc diet during pregnancy and up to weaning. Afterward, offspring were fed either a low- or a control zinc diet until 81 days of life. IL-6 and TNF-α levels, TUNEL assay, TGF-ß1 expression, thiobarbituric acid-reactive substances that determine lipoperoxidation damage, NADPH oxidase-dependent superoxide anion production, antioxidant and nitric oxide synthase activity, mRNA and protein expression of endothelial nitric oxide synthase, and serine1177 phosphorylation isoform were determined in left ventricle. RESULTS: Zinc deficiency activated apoptotic and inflammatory processes and decreased TGF-ß1 expression and nitric oxide synthase activity in cardiac tissue of both sexes. Male zinc-deficient rats showed no changes in endothelial nitric oxide synthase expression, but a lower serine1177 phosphorylation. Zinc deficiency induced an increase in antioxidant enzymes activity and no differences in lipoperoxidation products levels in males. Females were less sensitive to this deficiency exhibiting lower increase in apoptosis, lower decrease in expression of TGF-ß1, and higher antioxidant and nitric oxide enzymes activities. A zinc-adequate diet during postnatal life reversed most of these mechanisms. CONCLUSION: Prenatal and postnatal zinc deficiency induces alterations in cardiac apoptotic, inflammatory, oxidative, and nitric oxide pathways that could predispose the onset of cardiovascular diseases in adult life.