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Follistatin is a binding protein and antagonist for activin, a member of the TGF-β family [23]. Follistatin is expressed in the deciduum, developing hindbrain, somites, vibrissae, teeth, epidermis and muscle. Follistatin deficient mice have been generated by targeted deletion of exons 1–6 of the encoding gene [24]. Follistatin knockout newborn mice are growth-retarded and have shiny, taut skin. They lack incisors, or have delayed incisor development, and sometimes have a cleft secondary palate or lack a hard palate, similar to activin-βA-deficient mice [25]. Their whiskers are thin and inappropriately oriented. In their vibrissae, teeth and palate, where follistatin is expressed adjacent to activin-βA, follistatin may play a role in activin signal transduction, possibly sequestering activins in heparan sulphate proteoglycans and presenting activin to activin receptors. The skin of follistatin knockout mice shows hyperkeratosis with thickened granular and stratum corneum layers, resembling the skin of transgenic mice with over-expression of TGF-β1 [26]. Abnormal expression of keratin 6 is evident in the interfollicular epidermis in follistatin knockout mice, as well as in the outer root sheaths of hair follicles, but mitotic activity is not increased. These mice have musculoskeletal abnormalities, such as decreases in muscle mass and defects in ribs and vertebrates, some of which are similar to those in the BMP-5 (short ear) mutant mice [27]. Thus, follistatin seems to be involved in signal transduction of TGF-β related proteins.
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Follistatin is a monomeric glycoprotein, existing in at least six molecular isoforms (ranging from 32 to 44 kDa). Like inhibin, it was first identified based on its ability to suppress the biosynthesis and secretion of FSH by pituitary cells [14, 52, 53]. Follistatin has been recognized as a binding protein for both inhibin and activin [54–57]. It binds to inhibin and activin through β-subunits, by which it influences the effect of inhibin and neutralizes the bioactivity of activin [58–61]. A recent study has shown that the action of follistatin is mediated through the inhibition of activin binding to the type II receptors, rather than to the interaction of the type I receptor with the activin/type II receptor complex [62].
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Follistatin
Follistatin is a glycoprotein and member of the TGF-β family that antagonizes many members of that family, including activin A, growth differentiation factor 11 (GDF-11), and GDF-8. Administration of that molecule produced an increase in body weight dependent on muscle mass in rats. It has also improved aggression and muscle atrophy, modulating the early response of the inflammatory phase by increasing macrophagic density and Pax7 + cells, accelerating the process of myofiber restoration and muscle function.75
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Follistatin
Follistatin is a binding protein that is locally produced in the gonads and pituitary, as well as other tissues, and functions to bind and neutralize members of the TGFβ superfamily. It negatively regulates Fshb transcription by binding activin and blocking its action on gonadotropes [94,105]. Follistatin knockout mice are born with multiple defects and die shortly after birth, and therefore gonadal development could not be assessed [110]. Therefore, in order to further study the role of follistatin, subsequent models have been designed utilizing a Cre/loxP conditional knockout mouse, as well as transplantation of follistatin-null mouse testes into immunocompromised mice [111,112]. In the Cre/loxP conditional knockout, the follistatin gene was deleted specifically in the granulosa cells of the ovary. In female mice, follistatin deletion resulted in varying degrees of infertility, reduced litter size and number, reduced ovarian follicles and ovulations, and elevated FSH and LH, similar to a premature ovarian insufficiency in humans [111]. In a separate study, fetal testes from follistatin-null mice were transplanted onto the external ear of castrated immunocompromised male mice [112]. After 7–8 weeks, spermatogenesis appeared normal and was comparable to spermatogenesis in mice that received transplantation of WT testes, suggesting that, in the absence of local follistatin production, circulating follistatin is sufficient to support spermatogenesis [112].
To further evaluate the role of follistatin on reproductive development, Guo et al. created a gain-of-function follistatin mutant mouse model [113]. Follistatin was overexpressed in multiple tissues using an mMT-1 promoter, which resulted in a viable MT-FS transgenic model [113]. Overexpression of follistatin resulted in live births, and fertile mice that survived to adulthood. Male MT-FS mice, however, displayed testis defects including decreased testis size, Leydig cell hyperplasia, and these mice eventually became infertile as a result of spermatogenic arrest [113]. Female MT-FS mice also became infertile overtime due to a block in folliculogenesis at varying stages, and developed thin uteri as well as small ovaries [113]. This study suggests follistatin likely acts locally, at the level of the gonad or the pituitary, by regulating activin signaling and/or other TGF-β family members.
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Follistatin
Follistatin (FST) is a glycosylated single-chain protein functionally (but not structurally) linked to the TGF-β superfamily of proteins. Secreted by granulosa cells, FST is an important regulator of cellular differentiation and secretion through its potent ability to bind and bioneutralize activin (a stimulator of FSH secretion with which it is colocalized in many tissue systems) and other members of the TGF-β superfamily.
The human follistatin (FST) gene is located at chromosome 5q11.2 and comprises 6 exons that encode a 344-amino-acid cysteine-rich protein. Exon 1 encodes a 29-amino-acid signal peptide, whose cleavage results in isoforms of 288 and 215 amino acids. The 288-amino-acid protein is composed of a 63-amino-acid N-terminal segment containing hydrophobic residues essential for activin binding, followed by 3 repeating 10-cysteine follistatin domains. Various 31- to 39-kD FST isoforms are generated by alternative splicing, glycosylation, and proteolytic cleavage. FST is highly conserved among species, with 97% amino acid homology between human and mouse.
FST functions as a downstream component of signaling by WNT4, a key antitestis factor involved in repressing testis development. Because the presence of oogonia is critical for survival and maturation of the ovary, FST, which promotes survival of oocytes and maintenance of oogenesis, appears to be an important factor in normal ovarian development. FST also antagonizes the action of activins and BMP15 on steroidogenesis in granulosa cells, probably via autocrine/paracrine mechanisms.
FST expression is tightly regulated during development, and its promoter contains binding sites for several transcription factors. In the mouse, Fst mRNA can be detected in somatic cells of fetal ovaries from E11.5, declining after E14.5. Fst is not expressed in Wnt4-null mice, indicating that Wnt4 likely regulates its expression. Fst-null XX mice have aberrant development of the coelomic blood vessel, a hallmark of testicular organogenesis, as well as prenatal loss of germ cells in the ovarian cortex. Thus the coordinated actions of Wnt4 and Fst appear to be key to suppression of testis development via inhibition of activin-driven coelomic vessel development.
Human FST mRNA expression is detectable by Northern blot in nearly all tissues examined, with the highest expression in adult ovary, and in undifferentiated and partially differentiated granulosa cells, the pituitary, kidney, and fetal heart and liver. FST is not detectable in the human fetal testis.
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FOLLISTATIN
Follistatin is a glycosylated protein which was originally isolated on the basis of its ability to suppress FSH secretion by pituitary cells in vitro, but it shows no structural similarity to the inhibins.5,6 There are differing forms, with molecular weights ranging from 31 to 44 kD, based on alternative splicing mechanisms of the five exons of the follistatin gene and the degree of glycosylation.29,30 However, two major forms are recognized because of their physiologic implications. Follistatin 288, a 288-amino-acid form has the capacity to bind avidly to heparan sulfate proteoglycans, whereas follistatin 315 does not demonstrate this property and represents the circulating form31,32 (reviewed in ref. 33). Follistatin 315 can be proteolytically processed in the ovary to follistatin 300 (300 amino acids). The capacity of follistatin to suppress FSH relates to its capability to bind and neutralize the biological activity of the activins, which in the context of the pituitary, is their ability to stimulate FSH.34 They have the capacity to neutralize all the actions of the activins.
The amino acid sequences of rat, mouse, human, bovine, ovine, and porcine follistatin are highly homologous (97%). No follistatin receptor has been identified. Because of the binding of follistatin to heparan sulfate proteoglycans, administration of heparin can release significant quantities of follistatin and bound activin into the circulation in both humans and sheep35 (Fig. 116-3). These studies indicate the presence of significant quantities of tissue stores linked to basement membranes, some of the activins being targeted through this pathway to intracellular degradation via lysosomal pathways.31
The heparin-binding site is critical to the capacity to neutralize the actions of endogenous activins, since a related molecule, follistatin-like protein 3, lacks this binding site and is a weak antagonist of endogenous activin despite being only slightly less potent in neutralizing exogenous activin.36
Consequences of Targeted Disruption of the Follistatin Gene
Knockout of the follistatin gene results in death within hours of birth due to respiratory failure related to weak diaphragmatic and thoracic musculature caused by the absence of follistatin's neutralization of the actions of myostatin.28 A more recent study indicates the existence of lung pathology involving thickened alveolar-capillary membranes.37
Knockout mice also showed shiny, taut skin, similar to that observed in mice overexpressing TGF-β1 in the epidermis.28 The transgenic mice had abnormal whiskers, a cleft hard palate, and abnormal lower incisors. Defects in axial skeletal components were noted in the ribs and vertebrae. This phenotype is consistent with the possibility that follistatin modulates the activities of multiple members of the TGF family as discussed previously.38
Further studies have identified that the prenatal development of their ovaries is abnormal, with a substantial decrease in the ovarian follicular pool.39 These data are consistent with the tissue-specific targeted disruption of the follistatin gene in granulosa cells.40 In an attempt to rescue the follistatin knockout phenotype by crossing these mice with mice transgenic for the human follistatin gene expressed under the native promoter and engineered to express either follistatin 288 or follistatin 315, several novel actions of follistatin were identified, including a role in angiogenesis affecting tail growth and the potential prevention of corpus luteum formation in the ovary and abnormal Müllerian duct development, in that the oviduct failed to develop.34
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2.2 Follistatin
Follistatin is a single chain glycosolated polypeptide structurally unrelated to the inhibin/activin proteins. Follistatin was originally isolated from ovarian fluid where it mimics the action of inhibin on FSH secretion although with lower potency (Ling et al., 1985; Robertson et al., 1987; Ueno et al., 1987). The follistatin gene consists of six exons with alternate binding sites that give rise to two major transcripts: a full length transcript encoding a 344 amino acid pre-pro-protein or a carboxy-shortened 317 amino acid form missing exon six. Mature peptides are follistatin 315 and follistatin 288. Both peptide forms are capable of alternate splicing, proteolytic cleavage and variable glycosylation, giving rise to other molecular weight forms in vivo.
Follistatin has a high affinity for activin and binding is almost irreversible, so that follistatin efficiently neutralizes the actions of activin A. The follistatin–activin complex is generally considered to consist of one activin and two follistatin molecules, indicating that binding is via the β-subunit (Schneyer et al., 1994). Follistatin therefore also binds to the single β subunit on inhibin but with much lower affinity. The different molecular weight isoforms of follistatin have differing affinity for the cell surface. A portion of the follistatin 288 protein has a region with strong affinity for heparin sulphate, whereas the longer follistatin 315 has little or no affinity for heparin (Schneyer et al., 1996; Hashimoto et al., 1997). This allows follistatin 288 to antagonize the effects of activins at a cellular level, acting like a pseudo-receptor thereby blocking ligand access to activin receptors. Conversely, activin bound to follistatin 315 appears to be the predominant circulating form. The exact function of this form of follistatin is currently unclear; it does not appear that follistatin 315 functions to transport serum activin as binding seems to be irreversible (Schneyer et al., 1996; Hashimoto et al., 1997).
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2.21 Follistatin (FS)
Follistatin (FS) is a protein with known anti-inflammatory and anti-fibrotic properties and has the potential to limit the severity of diseases associated with inflammation and fibrosis such as capsular contracture. It is a specific binding protein for activin which neutralizes the diverse actions of activin by forming an inactive complex with activin [56,57].
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1 Introduction
Follistatin was identified in 1987 as a soluble protein in follicular fluid (Ueno et al., 1987) and was later recognised to be present in the circulation (Sugawara et al., 1990). Due to its ability to suppress the follicle stimulating hormone (FSH), it was named follistatin. The physiological role of circulating follistatin is incompletely understood: The current and predominant view is that follistatin is secreted by a broad selection of cell types and that plasma follistatin levels are the sum of the spill-over from paracrine/autocrine actions. Especially in the setting of reproductive physiology and inflammation, large efforts have been made to understand the role of circulating follistatin. Recently, it was demonstrated that the liver is a key contributor to the circulating levels of follistatin in humans, and that circulating follistatin is acutely regulated by the glucagon-to-insulin ratio in humans (Hansen et al., 2015a), which is supported by in vitro observations where primary rat and human hepatocytes secrete follistatin when stimulated with glucagon (Hansen et al., 2015a; Zhang et al., 1997). The aim of this article is to review circulating follistatin in physiological and pathophysiological conditions related to energy metabolism.
In humans, the gene encoding follistatin is located on chromosome 5q11.2 (Bondestam et al., 1999). The follistatin protein contains a TGF-β binding site where activins (Harrington et al., 2006; Shimonaka et al., 1991), bone morphonegic proteins (BMPs) (Pentek et al., 2009; Otsuka et al., 2001) and growth differentiation factors (GDFs) (Amthor et al., 2004; Cash et al., 2009) are bound with high affinity and thereby neutralised. The ligand binding site for follistatin overlaps with the type I and type II receptor binding sites for these ligands (Thompson et al., 2005). Follistatin also contains a heparin binding site (Inouye et al., 1992; Innis and Hyvonen, 2003) where proteoglycans in the extracellular matrix can bind, and therefore follistatin is believed to bind the extracellular matrix. Follistatin exists in two isoforms: follistatin 288 and follistatin 315, named after the number of amino acids contained in the single peptide. The two isoforms arise from alternative splicing (Shimasaki et al., 1988); the 315 isoform includes a 27 amino acid acidic C-terminal tail, which follistatin 288 does not have. The acidic tail on follistatin 315 neutralises the heparin binding site, thereby inhibiting the binding of follistatin 315 to the extracellular matrix (Lerch et al., 2007). Follistatin 315 is therefore estimated to be the predominant isoform found in the circulation (Schneyer et al., 2004), however no direct comparison has been performed. As heparin only binds follistatin 315 when a member of the TGF-β super family (activin, GDF-8 or BMP) also binds it (Lerch et al., 2007), this could mediate the clearance of the ligand-follistatin complex.
The finding that the liver contributes to the circulating levels is based on a commercially available assay that measures all the different isoforms of follistatin (288, 300 and 315). Follistatin 315 has been suggested to be the predominant circulatory isoform, whereas follistatin 288 has been characterised as acting within the tissue. The idea that particularly follistatin 315 has endocrine effects has been suggested previously (Takamura et al., 2005). Several “in house” assays have been used and an assay specific for follistatin 315 has been established, however no assay specific for follistatin 288 isoform has been reported. Thus, a comparison between 315 and 288 determining the plasma distribution of the two follistatin isoforms has not been possible. That plasma follistatin exists as a free and bound form adds to the degree of complexity. The level of free circulating follistatin has been assessed to <10% (McConnell et al., 1998) and up to 24% (Sakamoto et al., 1996) of total follistatin. Thus several aspects have to be considered when interpreting circulating follistatin. The function of follistatin has still not been determined. Genetical removal of follistatin leads to perinatal death in mice (Matzuk et al., 1995). Interestingly, follistatin KO mice can be rescued when human follistatin 315 is co-expressed; however co-expressing human 288 does not rescued the follistatin KO mouse (Lin et al., 2008). In contrast to this finding, a follistatin 288-only mouse (lacking the 315 isoform) surprisingly survived (Kimura et al., 2010). Thus, the function of the follistatin isoforms on a simple factor as vitality is not yet understood. The identification of the liver as the main contributor to circulating follistatin under the regulation of glucagon-to-insulin ratio (Hansen et al., 2015a) could suggest that circulating follistatin is related to energy metabolism, which made us review the existing observations on circulating follistatin in this new light.
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Follistatin
The follistatin family of proteins are a group of secreted glycoproteins that bind and neutralize TGF-β family factors. Cardiac synthesis of follistatin-like 1 (FSTL1) and 3 (FSTL3) are elevated in human heart failure and in rat models of hypertrophic cardiomyopathy induced by pressure overload (97). Serum FSTL1 is increased in patients with heart failure and acute coronary syndrome (98,99); therefore, it is a potential biomarker for cardiovascular diseases (98,100). FSTL1 administration has been shown to reduce myocardial infarct size in ischemia/reperfusion injury models through suppressing TGF-β family protein BMP4 proinflammatory signaling (101). In addition, FSTL1 overexpression specifically in mouse hearts leads to resistance to pressure overload−induced hypertrophy. Cardiomyocyte-specific loss of FSTL1 exacerbates cardiac hypertrophy and heart dysfunction while not altering the basal phenotype (122). In contrast to the beneficial role of FSTL1, FSTL3 binds activin A and antagonizes its cardiac protective function. As a result, cardiac-specific loss of FSTL3 attenuates ischemia/reperfusion injury and pathological hypertrophy (78,102).
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