Sertoli cells are somatic cells present in seminiferous tubules which have essential roles in regulating spermatogenesis. Considering that each Sertoli cell is able to support a limited number of germ cells, the final number of Sertoli cells reached during the proliferative period determines sperm production capacity. Only immature Sertoli cells, which have not established the blood-testis barrier, proliferate. A number of hormonal cues regulate Sertoli cell proliferation. Among them, FSH, the insulin family of growth factors, activin, and cytokines action must be highlighted. It has been demonstrated that cAMP/PKA, ERK1/2, PI3K/Akt, and mTORC1/p70SK6 pathways are the main signal transduction pathways involved in Sertoli cell proliferation. Additionally, c-Myc and hypoxia inducible factor are transcription factors which participate in the induction by FSH of various genes of relevance in cell cycle progression. Cessation of proliferation is a pre-requisite to Sertoli cell maturation accompanied by the establishment of the blood-testis barrier. With respect to this barrier, the participation of androgens, estrogens, thyroid hormones, retinoic acid and opioids has been reported. Additionally, two central enzymes that are involved in sensing cell energy status have been associated with the suppression of Sertoli cell proliferation, namely AMPK and Sirtuin 1 (SIRT1). Among the molecular mechanisms involved in the cessation of proliferation and in the maturation of Sertoli cells, it is worth mentioning the up-regulation of the cell cycle inhibitors p21Cip1, p27Kip, and p19INK4, and of the gap junction protein connexin 43. A decrease in Sertoli cell proliferation due to administration of certain therapeutic drugs and exposure to xenobiotic agents before puberty has been experimentally demonstrated. This review focuses on the hormones, locally produced factors, signal transduction pathways, and molecular mechanisms controlling Sertoli cell proliferation and maturation. The comprehension of how the final number of Sertoli cells in adulthood is established constitutes a pre-requisite to understand the underlying causes responsible for the progressive decrease in sperm production that has been observed during the last 50 years in humans.

Sertoli cells provide the structural and nutritional support for germ cell development; they actively metabolize glucose and convert it to lactate, which is an important source of energy for germ cells. Furthermore, Sertoli cells can oxidize fatty acids, a metabolic process that is assumed to fulfill their own energy requirements. Fatty acids are stored as triacylglycerides within lipid droplets. The regulation of fatty acid storage in conjunction with the regulation of lactate production may thus be relevant to seminiferous tubule physiology. Our aim is to evaluate a possible means of regulation by the PPARγ activation of lipid droplet formation and lactate production. Sertoli cell cultures obtained from 20-day-old rats were incubated with Rosiglitazone (10 μM), a PPARγ activator, for various periods of time (6, 12, 24 and 48 h). Increased triacylglycerides levels and lipid droplet content were observed, accompanied by a rise in the expression of genes for proteins involved in fatty acid storage, such as the fatty acid transporter Cd36, glycerol-3-phosphate-acyltransferases 1 and 3, diacylglycerol acyltransferase 1 and perilipins 1, 2 and 3, all proteins that participate in lipid droplet formation and stabilization. However, PPARγ activation increased lactate production, accompanied by an augmentation in glucose uptake and Glut2 expression. These results taken together suggest that PPARγ activation in Sertoli cells participates in the regulation of lipid storage and lactate production thereby ensuring simultaneously the energetic metabolism for the Sertoli and germ cells.

Sertoli cells play a central role in spermatogenesis. They maintain the blood-testis barrier, an essential feature of seminiferous tubules which creates the proper environment for the occurrence of the spermatogenesis. However, this confinement renders germ cells almost exclusively dependent on Sertoli cells' nursing function and support. Throughout spermatogenesis, differentiating sperm cells become more specialized, and their biochemical machinery is insufficient to meet their metabolic demands. Although the needs are not the same at all differentiation stages, Sertoli cells are able to satisfy their needs. In order to maintain the seminiferous tubule energetic homeostasis, Sertoli cells react in response to several metabolic stimuli, through signaling cascades. The AMP-activated kinase, sensitive to the global energetic status; the hypoxia-inducible factors, sensitive to oxygen concentration; and the peroxisome proliferator-activated receptors, sensitive to fatty acid availability, are pathways already described in Sertoli cells. These cells' metabolism also reflects the whole-body metabolic dynamics. Metabolic diseases, including obesity and type II diabetes mellitus, induce changes that, both directly and indirectly, affect Sertoli cell function and, ultimately, (dys)function in male reproductive health. Insulin resistance, increased estrogen synthesis, vascular disease, and pubic fat accumulation are examples of metabolic-related conditions that affect male fertility potential. On the other hand, malnutrition can also induce negative effects on male sexual function. In this chapter, we review the molecular mechanisms associated with the nutritional state and male sexual (dys)function and the central role played by the Sertoli cells.