Abstract
In Brief
Hormones secreted by muscle cells (myokines) are involved in the adaptive response to nutritional and metabolic changes. In this review, we discuss how one family of myokines may alter fertility in response to sudden changes in energy balance.
Abtract
Dietary stress such as obesity and short-term changes in energy balance can disrupt ovarian function leading to infertility. Adipose tissue secretes hormones (adipokines), such as leptin and adiponectin, that are known to alter ovarian function. Muscles can also secrete endocrine factors, and one such family of myokines, the eleven Fibronectin type III domain-containing (FNDC) proteins, is emerging as important for energy sensing and homeostasis. In this review, we summarize the known roles the FNDC proteins play in energy homeostasis and explore potential impacts on fertility in females. The most well-known member, FNDC5, is the precursor of the ‘exercise hormone’, irisin, secreted by both muscle and adipose tissue. The receptors for irisin are integrins, and it has recently been shown to alter steroidogenesis in ovarian granulosa cells although the effects appear to be species or context specific, and irisin may improve uterine and placental function in women and rodent models. Another member, FNDC4, is also cleaved to release a bioactive protein that modulates insulin sensitivity in peripheral tissues and whose receptor, ADGRF5, is expressed in the ovary. As obese women and farm animals in negative energy balance (NEB) both have altered insulin sensitivity, secreted FNDC4 may impact ovarian function. We propose a model in which NEB or dietary imbalance alters plasma irisin and secreted FNDC4 concentrations, which then act on the ovary through their cognate receptors to reduce granulosa cell proliferation and follicle health. Research into these molecules will increase our understanding of energy sensing and fertility and may lead to new approaches to alleviate post-partum infertility.
Introduction
Fertility in females is dependent, among other things, on nutritional status including energy reserves. It is well known that obesity reduces fertility in women and, conversely, too little body fat, either through anorexia or in high-performance atheletes, results in amenorrhea, anovulation and pregnancy failure (Boutari et al. 2020). In farm animals, liveweight or body condition (as a measure of fat reserves) are linked to the age of puberty in cattle and pigs (D’Occhio et al. 2019, Lents 2019). Some species are highly sensitive to short-term changes in energy balance, which is particularly evident during early lactation in pigs and dairy cattle (Roche et al. 2017, Costermans et al. 2020). The energy requirements for milk production exceed energy intake, and the resulting negative energy balance (NEB) drives the mobilization of body fat and in extreme cases muscle tissue.
Many sensors of low- or high-energy status involve the hypothalamo-pituitary axis, such as kisspeptin (Lents 2019), but adipose tissue also signals to the gonads through the secretion of adipokines. The roles of numerous adipokines on the reproductive system, including leptin, adiponectin, visfatin and chemerin, have been reviewed (Reverchon et al. 2014a, Estienne et al. 2019).
During NEB, the mobilization of fat reserves alters adipokine secretion, for example, plasma adiponectin and leptin concentrations have been observed to decrease at parturition in cattle (Mellouk et al. 2017), whereas plasma resistin and chemerin concentrations increase (Reverchon et al. 2014b, Mellouk et al. 2019). All these adipokines are also able to modulate in vitro ovarian steroidogenesis (Kurowska et al. 2021). Less well explored are growth factors expressed in muscle tissue (myokines) including insulin-like growth factor-1 (IGF1) and myostatin. Abundance of mRNA encoding IGF1 in muscle tissue increases in cattle postpartum whereas myostatin mRNA levels decrease (Mann et al. 2016). Interestingly, myostatin is expressed in the bovine ovary and suppressed estradiol secretion from granulosa cells (Cheewasopit et al. 2018).
Another adipokine/myokine family that has not been well explored in the context of fertility is the fibronectin type III domain-containing (FNDC) proteins, containing the so-called exercise hormone, irisin. The family includes FNDC1, FNDC3A, FNDC3B, FNDC4, FNDC5, FNDC6, FNDC7, FNDC8, FNDC9, FNDC10 and FNDC11. They are transmembrane proteins that may act in part as receptors for fibronectin, one of the proteins of the extracellular matrix, and may regulate the organization of an actin-containing cytoskeleton and signal transduction (Tominaga et al. 2004), and their various functions include tissue development and cell adhesion, migration and proliferation (Wuensch et al. 2019). However, two members, FNDC4 and FNDC5, are also cleaved to release circulating bioactive molecules although the importance of cleaved forms, in particular FNDC5, is controversial (Albrecht et al. 2020, Nie et al. 2020). The cleaved form of FNDC5, irisin, was discovered in 2012 as a muscle-derived hormone that regulates thermogenesis in adipose tissue in response to cold and exercise (Boström et al. 2012), and the potential effects of irisin on the reproductive axis are now being explored (Sengupta et al. 2021). The purpose of this review is to summarize the known patterns of expression and action of FNDC family members and to pose new questions about the role they may play in the nutrition–reproduction interface in females.
FNDC5 and irisin
The description of irisin in 2012 as an ‘exercise hormone’ in humans (Boström et al. 2012) led to intensive research on the secretion and action of this myokine. Many reviews have summarized the role of irisin in adipogenesis (Pyrżak et al. 2015) and metabolism (Jandova et al. 2021) and this information will not be reported here. The following sections focus on the energy sensing and female reproductive aspects of FNDC5/irisin biology.
Structure
Fndc5 was identified at the same time as Fndc4 as a protein with 60% identity in the FNIII domain and 86% identity in the transmembrane domain with mouse Fndc4. In mammals, the length of FNDC5 varies between 1573 and 3022 bp. Sequence homology is 96–100% between humans and rhesus monkeys, and 61–65 and 78% between humans and cattle and mice, respectively.
The FNDC5 protein, also called FRCP2, has an N-terminal sequence, an irisin domain, a short transmembrane region and a cytosolic C-terminal domain (Fig. 1) (Teufel et al. 2002). FNDC5 is synthesized in the form of a type I transmembrane protein of approximately 25 kDa molecular weight and is N-glycosylated at asparagines 36 and 81 (Nie & Liu 2017). It has been suggested that the full-length transmembrane protein can act as a receptor and plays a critical role in the differentiation of myoblasts and neurons (Teufel et al. 2002, Schumacher et al. 2013).
Simplified structure of FNDC family members. The proteins are characterized by the presence of a variable number of Fibronectin type III domains (FN3). FNDC3A and FNDC3B also contain a proline-rich region (PRR), and transmembrane FNDC4 and FNDC5 can be cleaved to release bioactive peptides. The numbers correspond to the amino acid position.
Citation: Reproduction 164, 1; 10.1530/REP-22-0037
Transmembrane FNDC5 can be cleaved to release a circulating bioactive molecule, irisin, a peptide of 112 amino acids and mass of 12.6 kDa containing an N-terminal FNIII-like domain (Boström et al. 2012). Plasma concentrations of irisin are reduced in conditions of rapid weight loss such as by bariatric surgery or dietary restriction in humans (Huh et al. 2012) and rats (Varela-Rodríguez et al. 2016), although other studies have not demonstrated an effect of adiposity on plasma irisin concentrations (Furino et al. 2021).
It should be noted however that there is controversy regarding the existence of this cleaved form in the peripheral circulation; proteolytic cleavage of the transmembrane protein has been demonstrated (Nie et al. 2020) whereas some studies have not been able to detect irisin in plasma of several species including cattle (Albrecht et al. 2020). Further work is needed to determine definitively whether irisin is a circulating hormone.
Tissue distribution
FNDC5 is highly expressed in muscle, salivary glands and heart and is more weakly expressed in other organ systems (Fig. 2). Within the reproductive system, FNDC5 transcripts have been detected in the mouse and chicken ovary (Li et al. 2015), porcine granulosa and theca cells (Basini et al. 2021) and the chicken and marmoset hypothalamus and pituitary gland (Li et al. 2015, Wahab et al. 2019).
Corporal localization of FNDC proteins in a model species, the pig. The data are derived from (Li et al. 2017) (NCBI) and data concerning endometrium and placenta are extrapolated from those available in the human protein atlas (www.proteinatlas.org) (Uhlén et al. 2015). The relative abundance of each FNDC protein is indicated by the size of the font.
Citation: Reproduction 164, 1; 10.1530/REP-22-0037
Function
Irisin acts through integrins as receptors, specifically αV (ITGAV) and β1 (ITGB1) (Kim et al. 2018), and its main role is to improve glucose uptake and reduce insulin resistance (Chen et al. 2016). In addition to its myokine activity, irisin can also act as an adipokine and is secreted from adipose tissue (Rabiee et al. 2020) and induces the browning of white adipose tissue via p38 and ERK signaling pathways by upregulating peroxisome proliferator-activated receptor-γ (PPARG) (Ma et al. 2019). The expression of FNDC5 is strictly dependent on the increased abundance of PPARG, especially during exercise. PPARG is a nuclear receptor that regulates fatty acid deposition, glucose metabolism and adipocyte differentiation, and is known to regulate genes in response to nutritional and physiological signals (Tominaga et al. 2004). Of interest here, PPARG is also expressed in the ovary and is important for granulosa cell development and regulation of steroidogenesis (Dupont et al. 2008).
Irisin/FNDC5 likely plays a role in fertility in females, as global deletion of Fndc5 results in disturbed estrous cycles and morphological abnormalities of the ovary in mice, and reduced plasma concentrations of estradiol, follicle-stimulating hormone and luteinizing hormone (LH) (Luo et al. 2021). Irisin appears to act on the hypothalamus–pituitary axis and on the ovary, and the data in the literature are conflicting. Irisin increased the release of gonadotrophin-releasing hormone (GNRH) from a mouse hypothalamic neuronal cell-line (Wahab et al. 2019) but intracerebroventricular injection of irisin decreased hypothalamic GNRH protein content in male rats (Tekin et al. 2019). The administration of exogenous irisin stimulated LH levels in obese female mice (Bastu et al. 2018) but the treatment of mouse pituitary mPit12 cells with irisin inhibited GNRH-dependent LH production (Poretsky et al. 2017). Systemic administration of irisin delayed puberty in female rats and increased ovarian fibrosis (Ulker et al. 2020).
Increased ovarian fibrosis is also observed in women with polycystic ovary syndrome (PCOS) accompanied by insulin resistance and hyperandrogenism, and serum irisin levels are higher in PCOS women compared with healthy women (Cai et al. 2018) and their follicular fluid contains higher levels of irisin. A few studies have investigated the effects of recombinant irisin on granulosa cells, with variable results. Treatment of human granulosa-lutein cells with irisin increased the production of estradiol in serum-containing medium (no insulin) but not in the presence of insulin (Poretsky et al. 2017), and irisin increased estradiol secretion from the KGN human granulosa cell line in medium with serum but no added insulin (Luo et al. 2021). However, irisin had no effect on estradiol secretion from pig granulosa cells in serum- and insulin-free medium (Basini et al. 2021). High concentrations of irisin decreased progesterone secretion from KGN and primary porcine granulosa cells (Basini et al. 2021, Luo et al. 2021), and low doses increased progesterone secretion from porcine granulosa cells (Basini et al. 2021). It seems likely that the effects of irisin are dependent on the energy balance of the experimental model, therefore cell cultures that take into account insulin and adipokine levels are required to understand better the role of irisin on granulosa cell function.
During pregnancy in women, plasma irisin concentrations increase and then decrease postpartum, and are reduced in preeclampsia and gestational diabetes (reviewed in Armistead et al. 2020). Addition of irisin to human placental explants promoted placental outgrowth and trophoblast differentiation through a pathway involving AMP-activated protein kinase (AMPK) (Drewlo et al. 2020), and irisin reduced apoptosis in human preeclamptic placenta explants through the Akt signaling pathway (Kohan-Ghadr et al. 2021). Circulating irisin concentrations are also elevated in women with endometriosis (Kaya Sezginer et al. 2022), and administration of irisin increased endometrial thickness in a rat model of PCOS (Li et al. 2019) and increased pregnancy rates in a rat model of mifepristone-induced implantation failure (Zhou et al. 2021), suggesting a positive effect of irisin on uterine receptivity. In cattle, plasma concentrations of various adipokines have been correlated with endometritis (Pereira et al. 2020), although any potential role of irisin in uterine function in cattle remains to be determined.
FNDC4
Structure
Teufel et al. (2002) cloned Fndc4 from a mouse bacterial artificial chromosome clone. The length of FNDC4 varies between 1451 and 2343 bp, depending on species, and consists of seven exons except for the chicken where Fndc4 has six exons. Some species express several isoforms as a result of splicing variation and alternative start and stop sites. Sequence homology is 98% between humans and rhesus monkeys, and 91 and 85–86% between humans and cattle and mice, respectively.
The FNDC4 protein (also known as FRCP1) is a 234 amino acid transmembrane protein containing an N-terminal signal peptide, a fibronectin type III domain at the cell surface and a transmembrane domain (Fig. 1). It has a molecular weight of approximately 25kDa and is N-glycosylated via an N-acetylglucosamine (GlcNAc) residue at amino acids 52, 97 and 147. As for FNDC5, mature transmembrane FNDC4 protein can be cleaved to release a smaller bioactive molecule (Bosma et al. 2016).
Tissue distribution
Northern blot analysis of mouse embryonic mRNA revealed strong expression of Fndc4 at embryonic day 11 and decreasing expression at E17 (Teufel et al. 2002). In adults, FNDC4 is most highly expressed in the liver and brain (Georgiadi et al. 2021) and moderately expressed in other organs systems including the endometrium and ovary (Fig. 2).
Function
FNDC4 exerts anti-inflammatory effects on macrophages and adipocytes in mice and improves insulin resistance (Bosma et al. 2016, Lee et al. 2018). Cleaved and secreted FNDC4 inhibits lipogenesis in vitro and promotes fat browning in human visceral adipocytes by acting via its receptor ADGRF5 (also known as GPR116) (Frühbeck et al. 2020). It has been demonstrated that secreted FNDC4 is produced mainly by the liver; knock-down of liver Fndc 4 in mice increased glucose intolerance and peripheral insulin resistance (Georgiadi et al. 2021). Further, weight loss in mice associated with improved insulin tolerance is accompanied by increased plasma FNDC4 concentrations in mice (Georgiadi et al. 2021).
Activation of ADGRF5 by FNDC4 leads to phosphorylation of AMPK and expression of heme oxygenase-1 (HMOX1) in adipocytes (Wuensch et al. 2019), which in turn suppresses inflammation and endoplasmic reticulum stress (Lee et al. 2018). Other mechanisms of action have also been proposed for FNDC4 signaling, including the Wnt/β-catenin signaling pathway through interaction with low-density lipoprotein receptor 6 (LRP6), a Wnt receptor, in the mouse myoblastic C2C12 cell line (Li et al. 2020), and through the ITGβ1 receptor and focal adhesion kinase (FAK) signaling in bovine skeletal muscle satellite cells (Wang et al. 2020).
The secreted form of FNDC4 may also act on the ovarian follicle, as a number of the receptors and pathways employed by FNDC4 described above are also present in granulosa cells, including ADGRF5 (Prömel et al. 2012), Frizzled and LRP6 (Tepekoy et al. 2019), fibronectin and FAK (Kitasaka et al. 2018), alphaV and beta1 integrins (Burns et al. 2002) and the energy sensor, AMPK (Horlock et al. 2021). As dairy cattle become insulin resistant during lactation (Bossaert et al. 2008), it is possible that altered secretion of FNDC4 may play a role to improve glucose uptake and mitigate the negative effects of NEB.
FNDC3A
Structure
In humans, there are two paralogs of FNDC3, termed FNDC3A and FNDC3B, which are located on different chromosomes and will be presented separately.
The length of FNDC3A varies between 3790 and 6325 bp and consists of 24–34 exons, depending on the species. Alternative start and stop sites result in two or three splice variants, again depending on species. Gene sequence homology is 96–98% between humans and rhesus monkeys and 91–92 and 85–86% between humans and cattle and mice, respectively.
The FNDC3A protein, also called HUGO (HUman Gene expressed in Odontoblasts) (Carrouel et al. 2008), has a molecular weight of approximately 132 kDa. FNDC3A is composed of nine type III fibronectin modules, forms a transmembrane helix at its C-terminus, and possesses an amino terminus rich in proline (PRR) (Fig. 1). There are acetylation sites at amino acid 384 and phosphorylation sites at amino acids 203, 207 and 213 (Dephoure et al. 2008). FNDC3A protein has multiple conserved WW-domain binding motifs in the N-terminal PRR that mediate specific interactions with protein ligands. The PRR of FNDC3A contains one group I (PPxY) and one group IV (p(S/T)P)WW-domain binding motifs that are conserved in all orthologs (Obholz et al. 2006).
Tissue distribution
FNDC3A is highly expressed in peripheral tissues (Fig. 2) and, within the reproductive system, in the uterus and placenta, as well as in the testis and the prostate gland (Obholz et al. 2006) (Fig. 2), but apparently not in the ovary (www.proteinatlas.org) although this requires experimental validation in animal models.
Function
FNDC3A is involved in organ development, including mammary gland development in mice; Fndc3a knock-out mice have mammary glands with enlarged fat pads and retarded development of the ductal network (Obholz et al. 2006). This knock-out model also displays increased lipid accumulation in the liver, suggesting that FNDC3A has multiple functions in lipid synthesis or mobilization.
FNDC3A protein is necessary for spermatogenesis in mice; it is present in Leydig cells and the acrosome of spermatids, and deletion of Fndc3a causes sterility in males likely by disrupting adhesion between spermatids and Sertoli cells (Obholz et al. 2006). Female Fndc3a mutant mice display a defect in secretion of lipid-containing vesicles from mammary epithelial cells but they are otherwise fertile (Obholz et al. 2006). Although FNDC3A has not been described in the ovary, its binding partner, FAM46C, is expressed in the pig ovary and mRNA abundance is lower in prolific compared to non-prolific sows (Fernandez-Rodriguez et al. 2011), so a role for FNDC3A in fertility is worthy of exploration.
FNDC3B
Structure
FNDC3B was discovered through a screen to identify gene expression during early adipocyte differentiation of 3T3-L1 mouse embryonic fibroblast cells (Nishizuka et al. 2009). The length of FNDC3B varies between 4828 and 8031 bp and consists of 27–31 exons, depending on the species. Some species express two (mouse and human) or five (rhesus monkey) variants which differ through alternative splicing and alternative start sites. Sequence homology is 97–98% between humans and rhesus monkeys and 93 and 85% between humans and cattle and mice, respectively.
The protein structure of FNDC3B, also called FAD104, is similar to that of FNDC3A and consists of nine fibronectin type III domains and an N-terminal proline-rich motif (Kishimoto et al. 2013) (Fig. 1). It has a hydrophobic C-terminal tail similar to those found in proteins such as Bcl-2 (Cai et al. 2012) and undergoes phosphorylation at amino acids 208, 393 and 1163 (Dephoure et al. 2008).
Tissue distribution
FNDC3B is highly expressed in white adipose tissue (Tominaga et al. 2004), and moderately expressed in other organ systems including endometrium and ovary, and the male reproductive tract (Fig. 2).
Function
Mice null for Fndc3b are cyanotic, fail to inflate the lungs despite attempting to breathe, and die within a few minutes of birth (Nishizuka et al. 2009). In mice, Fndc3b is most strongly expressed during adipocyte differentiation, and knock-down of Fndc3b decreased adipocyte triacylglycerol concentrations, strongly suggesting an important role in adipogenesis (Tominaga et al. 2004).
FNDC3B is also important for embryonic bone development and negatively regulates osteoblast formation in mouse embryonic fibroblasts (Kishimoto et al. 2013). FNDC3B may also play roles in cancer development and is highly expressed in cancers of the uterus, ovary and breast (Cai et al. 2012, Wuensch et al. 2019). Both FNDC3A and FNDC3B have been located in the placenta (Obholz et al. 2006), although a specific function has not been described. Several adipokines have been shown to alter placental nutrient transfer and fetal growth, including leptin (Nguyen-Ngo et al. 2020), therefore a role can be proposed for FNDC3A and/or FNDC3B in fatty acid transport across the placenta.
FNDC1
Structure
Sato et al. (2006) cloned Fndc1 from a rat heart cDNA library by RT-PCR, which they designated Ags8 (Activator of G-protein Signaling 8). The length of FNDC1 varies between 6562 and 5597 bp and consists of 20–24 exons depending on the species. Some species express two (cattle) or three (rhesus monkey) isoforms. Gene sequence homology is 96% between humans and rhesus monkeys and 80 and 76% between humans and cattle and mice, respectively.
The protein encoded by FNDC1, also called KIAA1866 or MEL4B3, contains 1894 amino acids in humans with minor variations between species, with an approximate molecular mass of 200 kDa. The protein consists of a signal peptide followed by five fibronectin type III domains (Fig. 1) and is a secreted or an intracellular protein according to the isoform (https://www.proteinatlas.org). FNDC1 is N-glycosylated with an GlcNAc residue at amino acids 149 and 1661.
Tissue distribution
In humans, FNDC1 is mostly expressed in muscles and more weakly in the reproductive system (endometrium, placenta, ovary, testis and prostate gland; Fig. 2).
Function
FNDC1 activates G protein signaling by forming complexes with the βγ subunit of the G protein and connexins, and has been previously described as a regulator of cardiovascular function (Sato et al. 2006) and is required for hypoxia-induced apoptosis in cardiomyocytes (Hayashi et al. 2016). In general, FNDC1 gene expression is linked with various cancers, including prostate cancer (Wuensch et al. 2019). This protein does not likely play a role in metabolism or energy sensing, and there are no reports of actions on the normal reproductive system.
Other FNDCs
The other FNDC family members, FNDC6, FNDC7, FNDC8, FNDC9, FNDC10 and FNDC11, have been less studied. They are well conserved phylogenetically and contain at least one FNIII motif. FNDC6, also called interleukin-20 receptor subunit β is a transmembrane protein with a molecular weight of 36.5 kDa that is expressed mainly in the peripheral digestive tract, skin, bone marrow, lymphoid tissues and female tissues (NCBI and Human Protein Atlas). Its signaling regulates the responses of CD8 and CD4 T lymphocytes and downregulates the T lymphocyte response to antigens (Wahl et al. 2009). FNDC7 has a molecular weight of 78.1 kDa and is mainly expressed in the brain, testis and oviduct (Voronina et al. 2019). FNDC8 has a molecular weight of 35.9 kDa and is mainly expressed in the testis; the function in the testis is unclear as knock-out mice appear fertile (Lu et al. 2019). The proteins FNDC9 and FNDC10, have molecular weights of approximately 25 kDa and are mainly expressed in brain and endocrine tissues. Finally, FNDC11 has a molecular weight of 36.5 kDa and is mainly expressed in human testis (www.proteinatlas.org). The function of these proteins has not been well explored, nor has any potential role in the reproductive system.
Conclusion
Short-term mobilization of adipose tissue, either due to famine, anorexia or onset of lactation, can drastically alter fatty acid and adipokine concentrations in blood, and impact the reproductive system. The evidence reviewed above suggests that irisin/FNDC5 protein and/or mRNA abundance are decreased by a sudden loss of adipose tissue in humans and rodent models, and that secreted FNDC4 concentrations are increased during weight loss associated with improvement of insulin tolerance. It is of interest to determine whether similar changes in plasma FNDC4 and irisin concentrations occur during NEB in cattle and pigs and to assess the impact of these myokines on reproductive function. A model can be proposed in which sudden mobilization of adipose tissue decreases FNDC5 secretion while increasing plasma FNDC4 concentrations (Fig. 3). Lower irisin concentrations may lead to reduced estradiol secretion and increased progesterone secretion, resulting in reduced granulosa cell proliferation and follicle health. Increased secreted FNDC4 concentrations however may improve glucose tolerance within the reproductive tract, but any direct effects on ovarian function remain to be determined. The balance of irisin, FNDC4 and other adipokine concentrations likely determines how the reproductive system senses energy status and contributes to fertility.
Hypothetical model for the actions of secreted FNDC4 and irisin in granulosa cells during rapid mobilization of adipose tissue. Loss of adipose tissue leads to decreased irisin secretion, lower activation of integrin signaling and reduced estradiol secretion and cell proliferation. On the other hand, insulin resistance increases plasma concentrations of secreted FNDC4, which acts through ADGRF5 to improve glucose tolerance and may impact granulosa cell health. The balance of these two myokines, along with the adipokines, likely dictates the response of the reproductive system to changes in energy balance.
Citation: Reproduction 164, 1; 10.1530/REP-22-0037
Declaration of interest
J Dupont is an Associate Editor and C A Price is a Co-Editor-in-Chief of Reproduction. J Dupont and C A Price were not involved in the review or editorial process for this paper, on which they are listed as authors. The other authors have nothing to disclose.
Funding
M D is supported by a grant to C A P from NSERC Canada.
Author contribution statement
M D wrote the manuscript and prepared the figures, Y B, J D and C A P conceived and revised the manuscript.
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