Follicle-Stimulating Hormone Activates Fatty Acid Amide Hydrolase by Protein Kinase A and Aromatase-Dependent Pathways in Mouse Primary Sertoli Cells

Abstract

Among the biological activities of the endocannabinoid anandamide (N-arachidonoylethanolamine) (AEA), growing interest has been attracted by the regulation of mammalian fertility. Recently we have shown that treatment of mouse primary Sertoli cells with FSH enhances the activity of the AEA hydrolase [fatty acid amide hydrolase (FAAH)], though the molecular details were not elucidated. Here, we investigated whether FSH was also able to affect the enzymes that synthesize AEA (N-acyltransferase and N-acyl-phosphatidyl-ethanolamine-phospholipase D), the endogenous content of this endocannabinoid, and the level of the AEA-binding vanilloid receptor 1 (transient receptor potential channel vanilloid receptor subunit 1). We show that FSH enhanced FAAH activity (up to approximately 500% of the controls) and expression (up to approximately 300%), leading to a marked reduction (down to approximately 15%) of AEA content. However N-acyltransferase and N-acyl-phosphatidyl-ethanolamine-phospholipase D activity, and transient receptor potential channel vanilloid receptor subunit 1 binding were not affected. We also show that diacylglycerol lipase and monoacylglycerol lipase, which respectively synthesize and degrade 2-arachidonoyl-glycerol, were not regulated by FSH, neither was the membrane transport of this endocannabinoid. In addition, we show that FAAH stimulation by FSH was abrogated by inhibitors of protein kinase A (PKA) and cytochrome-P(450) aromatase, and was conversely mimicked by N,O'-dibutyryl cAMP and estrogen. Finally, we demonstrate that FSH protects Sertoli cells against the pro-apoptotic activity of AEA, through PKA and aromatase-dependent activation of FAAH. Altogether these data suggest that FAAH is the only target of FSH among the elements of the endocannabinoid system, and that its regulation by PKA and aromatase-dependent pathways impacts Sertoli cell proliferation.

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

“…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].…”

“…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].…”

“…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].…”

“…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]. Aromatase activation leads to the conversion of androgens to estrogens with the production of E 2 , which stimulates FAAH expression at the transcriptional and translational level by unknown molecular mechanisms [15].…”

“…FSH regulates FAAH expression and activity by triggering both protein kinase A-and aromatase-dependent transduction pathways [15]. Aromatase activation leads to the conversion of androgens to estrogens with the production of E 2 , which stimulates FAAH expression at the transcriptional and translational level by unknown molecular mechanisms [15].…”