Anandamide Activity and Degradation Are Regulated by Early Postnatal Aging and Follicle-Stimulating Hormone in Mouse Sertoli Cells

Abstract

Anandamide (AEA), a prominent member of the endogenous ligands of cannabinoid receptors (endocannabinoids), is known to adversely affect female fertility. However, a potential role of AEA in male reproductive functions is unknown. Here we report evidence that immature mouse Sertoli cells have the biochemical tools to bind and inactivate AEA, i.e. a functional type-2 cannabinoid receptor (CB2R), a selective AEA membrane transporter, and an AEA-degrading enzyme fatty acid amide hydrolase. We show that, unlike CB2R, the activity of AEA membrane transporter and the activity and expression of FAAH decrease, whereas the apoptosis-inducing activity of AEA increases with age during the neonatal period. We also show that FSH reduces the apoptotic potential of AEA, but not that of its nonhydrolyzable analog methanandamide. Concomitantly, FSH enhances FAAH activity in a manner dependent on mRNA transcription and protein synthesis and apparently involving cAMP. These data demonstrate that Sertoli cells partake in the peripheral endocannabinoid system, and that FSH reduces the apoptotic potential of AEA by activating FAAH. Taken together, it can be suggested that the endocannabinoid network plays a role in the hormonal regulation of male fertility.

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“…CB2 was found in Sertoli cells while other components of the ECS, such as AEA, FAAH, and EMT have also been observed in testicular tissues [4,19,49,56]. For example, administration of AEA, which usually binds to postsynaptic CB1 receptors, decreased serum LH.…”

“…Interestingly, studies showed that the CB2 receptor can also play a protective role by decreasing programmed cell death [62]. Activation of CB2 receptors protects Sertoli cells against AEA-induced/mediated apoptosis [49,62].…”

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“…Indeed, it has been demonstrated that FAAH expression and activity in Sertoli cells decrease in an age-dependent manner [14]. To ascertain whether regulation of FAAH expression by E 2 was modified during postnatal development, we analyzed by qRT-PCR FAAH mRNA expression in Sertoli cells obtained from 7-day-old mice.…”

“…These substances play manifold roles in both the central nervous system and in the periphery [10,11], reproductive organs included [12], mainly by activating G-protein coupled type-1 (CB 1 ) and type-2 (CB 2 ) cannabinoid receptors [13]. In the seminiferous tubules of the testis, both germ cells and somatic Sertoli cells possess a complete biochemical machinery to synthesize, transport, degrade and bind AEA and 2-arachidonoylglycerol [14][15][16]. Both endocannabinoids affect male reproductive functions: 2-arachidonoylglycerol has a pivotal role in spermatogenesis, by promoting the meiotic progression of germ cells [16]; AEA controls sperm functionality by reducing motility, capacitation, and acrosome reaction [17,18], and it also reduces the spermatogenic output by inducing apoptosis of Sertoli cells [15].…”

“…AEA signaling depends on its endogenous content, that in vivo is strongly controlled by FAAH [19]. Remarkably, recent studies have shown that among the different components of the ''endocannabinoid system'' (i.e., AEA-binding receptors and metabolic enzymes) in Sertoli cells, only FAAH is a target of follicle-stimulating hormone (FSH) [14,15]. FSH regulates FAAH expression and activity by triggering both protein kinase A-and aromatase-dependent transduction pathways [15].…”