199 REVIEW Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition P Froment, F Gizard1, D Defever2, B Staels1, J Dupont3 and P Monget3 INSERM U.418, UMR Communications Cellulaire et Différenciation, Hôpital Debrousse, 29 rue Soeur Bouvier, 69322 Lyon, France 1INSERM U.545, Institut Pasteur de Lille et Faculté de Pharmacie Université de Lille 2, 1 rue du Pr Calmette, 59019 Lille, France 2LMCB, Department of Molecular Biomedical Research, V.I.B., Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium 3Physiologie de la reproduction et des comportements, UMR 6175 INRA-CNRS-Université F. Rabelais de Tours-Haras Nationaux, 37380 Nouzilly, France (Requests for offprints should be addressed to P Froment; [email protected]) Abstract Peroxisome proliferator-activated receptors (PPAR, granulosa cell proliferation and steroidogenesis in vitro. All PPAR/ and PPAR) are a family of nuclear receptors these recent data raise new questions about the biologic that are activated by binding of natural ligands, such as actions of PPARs in reproduction and their use in polyunsaturated fatty acids or by synthetic ligands. Syn- therapeutic treatments of fertility troubles such as PCOS thetic molecules of the glitazone family, which bind to or endometriosis. In this review, we first describe the roles PPAR, are currently used to treat type II diabetes and of PPARs in different compartments of the reproductive also to attenuate the secondary clinical symptoms fre- axis (from male and female gametogenesis to parturition), quently associated with insulin resistance, including poly- with a focus on PPAR. Secondly, we discuss the possible cystic ovary syndrome (PCOS). PPARs are expressed molecular mechanisms underlying the effect of glitazones in different compartments of the reproductive system on PCOS. Like other ‘insulin sensitizer’ molecules, such (hypothalamus, pituitary, ovary, uterus and testis). Con- as metformin, glitazones may in fact act directly on servative functions of PPARs in mammalian species could ovarian cells. Finally, we discuss the eventual actions of be suggested through several in vivo and in vitro studies, PPARs as mediators of environmental toxic substances for especially in the ovary and during placental development. reproductive function. Several groups have described a strong expression of Journal of Endocrinology (2006) 189, 199–209 PPAR in ovarian granulosa cells, and glitazones modulate Introduction Since the discovery of PPARs in 1990 (Issemann & Green 1990), numerous functions have been attributed to PPAR is a nuclear receptor of the peroxisome proliferator- these receptors. In addition to enhancing insulin sensi- activated receptor family, which also includes PPAR and tivity, PPAR has been shown to regulate fat mass and cell PPAR/ (for review, see Sorensen et al. 1998, Desvergne proliferation (Debril et al. 2001) and to modulate inflam- & Wahli 1999). PPAR is activated after the binding of matory reactions. Three PPAR isoforms are expressed in natural ligands such as polyunsaturated fatty acids and the central nervous system and in the following repro- prostaglandin metabolites. It can also be activated by syn- ductive tissues: gonads (ovary, testis), uterus, prostate, thetic ligands such as thiazolidinediones (TZDs), also mammary gland and pituitary gland (Komar et al. 2001, known as glitazones (rosiglitazone, pioglitazone or troglita- Froment et al. 2003, Mouihate et al. 2004). zone) (Lehmann et al. 1995). The binding of TZDs to their Fuel sensors, such as glucose, insulin or leptin, are receptors increases insulin sensitivity, and most bind primar- known to be directly involved in the regulation of fertility ily to PPAR in adipose cells. TZDs are frequently admin- at each level of the hypothalamo-pituitary-gonad axis istered to patients with insulin resistance associated with (for review, see Poretsky et al. 1999, Froment et al. 2001). type II diabetes (for review, see Houseknecht et al. 2002, For example, mice lacking insulin-signaling pathway Gurnell et al. 2003, Staels & Fruchart 2005). components, such as insulin receptor substrate 2 (IRS-2) Journal of Endocrinology (2006) 189, 199–209 DOI: 10.1677/joe.1.06667 0022–0795/06/0189–199 2006 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 10/02/2021 05:41:05PM via free access 200 P FROMENT and others · PPARs in reproductive function or insulin receptor, exhibit female and male infertility do not seem to play an important role in fertility. Indeed, (Bruning et al. 2000, Burks et al. 2000). PPAR activation PPAR- and PPAR/-null mice are viable and fertile modifies the transcription and/or activity of different key (Lee et al. 1995, Peters et al. 2000). Xenobiotic ligands of regulators of energy homeostasis (Devergne & Wahli PPAR and PPAR induce the translocation of these 1999), for example stimulation of several glucose regula- receptors to the nucleus of Sertoli cells (Bhattacharya et al. tors (glucose transporters, insulin receptor, IRS, etc.) (for 2005). PPAR is also more strongly expressed in human review, see Picard & Auwerx 2002). We can hypothesize testicular cancer cells than in normal testicular tissues. that PPAR acts also as a fuel sensor in reproductive PPAR ligands (TZDs or 15d-PGJ2) have antiprolifera- compartments to inform cells on the energy status. In this tive effects on testicular cancer cells (Hase et al. 2002). In case, PPAR may be a link between energy metabolism addition, the incubation of testicular tissue with TZDs and reproduction, as in polycystic ovary syndrome induces a decrease in the level of mRNA for resistin, (PCOS), which is frequently associated with insulin which impairs insulin sensitivity and glucose tolerance resistance. (Nogueiras et al. 2004). The expression of PPAR is upregulated by FSH (Schultz et al. 1999), a key hormone that also stimulates the production of testicular fluid Expression and putative roles of PPARs in components, protein synthesis and the mobilization of reproductive tissues energy sources. PPAR may play a physiologic role in steroidogenesis (see below, under heading ‘PPARs – Hypothalamic-pituitary axis mediators of endocrine disruptors of environmental origin?’) and may influence the fertility of spermatozoa. In the last 3 years, several teams have demonstrated Indeed, PPAR regulates the beta-oxidation of lipids and PPAR expression in the pituitary gland (mouse and may also regulate the fatty acid composition of phospho- sheep) (Heaney et al. 2003, Mouihate et al. 2004) and in lipids in germ cells. The lipid composition of spermatozoa the hypothalamus (rat) (Mouihate et al. 2004). PPAR has ff is known to modulate their mobility and its viability antiproliferative e ects in pituitary cells (Heaney et al. (Douard et al. 2003). 2003), and the administration of TZDs inhibits the development of pituitary adenomas in mice and man. Moreover, PPAR expression in the pituitary gland may decrease by about 54% after 24 h of restricted food intake Ovary (Wiesner et al. 2004). In the human hypothalamus, PPAR may play a role in Expression and localization (Fig. 1a and b) The temperature regulation, as its natural ligand is 15d-PGJ2 PPAR and PPAR/ isoforms are expressed primarily in (15-deoxy-delta12,14-prostaglandin J ), which is secreted the theca and stroma tissues. PPAR deletion has no 2 apparent effect on the fertility of mice, but the deletion of into the cerebrospinal fluid (Mouihate et al. 2004). ff Despite its presence in these organs, PPAR does not PPAR and PPAR/ does have this e ect (Lee et al. seem to affect reproductive function at this level of 1995, Peters et al. 2000, Barak et al. 2002). In the ovaries signaling. Indeed, in vitro, the secretion of ovine pituitary of rodents and ruminants, PPAR is expressed strongly in hormones, including PRL (prolactin), GH (growth the granulosa cells, and less strongly in the theca cells and hormone), FSH (follicle-stimulating hormone) and LH corpus luteum (Gasic et al. 1998, Komar et al. 2001, (luteinizing hormone), and LH secretion by murine Froment et al. 2003). PPAR is detected early in follicu- LbetaT2 gonadotropic pituitary tumor cells do not seem logenesis, at the primary/secondary follicle stage (Komar to be affected by TZD treatment (Froment et al. 2003). 2005). PPAR expression increases until the large follicle stage (Froment et al. 2003, Komar 2005), and decreases after the LH surge (Komar et al. 2001) (Fig. 1a and b). Testis In the testis, the three PPAR isoforms are expressed in PPAR action on steroidogenesis and proliferation both somatic and germ cells (Braissant et al. 1996, Elbrecht during folliculogenesis Several studies have shown that et al. 1996, Bhattacharya et al. 2005). PPAR and TZDs present contradictory actions on secretion of PPAR/ are widely expressed in interstitial Leydig cells steroids (inhibition or stimulation of progesterone and and seminiferous tubule cells (Sertoli and germ cells) estradiol production) in granulosa cells (Fig. 1c). (Braissant et al. 1996, Schultz et al. 1999). On the other Thus, TZDs stimulate in vitro the secretion of steroids hand, PPAR is thought to be restricted to Sertoli cells (progesterone and estradiol) by rat and ovine granulosa (Elbrecht et al. 1996, Corton & Lapinskas 2005). How- cells (Komar et al. 2001, Froment et al. 2003), bovine ever, Thomas et al. (2005) recently detected PPAR lutein cells (theca- and granulosa-derived cells) (Lohrke mRNA in germ cells (spermatocytes) (Fig. 1d). The et al. 1998) and porcine theca cells (Schoppee et al. 2002), action of PPARs in the testis is unclear, but these receptors whereas they inhibit the secretion of progesterone and Journal of Endocrinology (2006) 189, 199–209 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 10/02/2021 05:41:05PM via free access www.endocrinology-journals.org PPARs in reproductive function Downloaded fromBioscientifica.com at10/02/202105:41:05PM Journal of Endocrinology · P FROMENT (2006) 189, and others 199–209 Figure 1 Expression of PPAR in gonads. (a) PPAR is strongly expressed in granulosa cells in primary to preovulatory follicles in the ovary (human, rat, mouse and ewe).