Adipokines and Reproduction in Ruminant Livestock
2024 Volume 12 Pages 13-23
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2024 Volume 12 Pages 13-23
An adipose tissue is the principal storage site for fat and secretes adipokines, including leptin, adiponectin, resistin, chemerin, visfatin, and apelin. Adipokines and their receptors have been demonstrated to be present and to play a role in the reproductive systems of various livestock species. Livestock reproductive function is thought to be influenced by adipokines, or hormones derived from adipokines. These adipokines have been implicated at all levels of the reproductive axis, including the hypothalamic-pituitary axis and gonads. Adipokines can amplify reproductive activity by increasing energy levels and triggering the production of essential reproductive hormones. The development of reproductive hormones, semen, estrus behavior, ovulation, and subsequent development of the corpus luteum and seminal concentrations are all regulated by adipokines. In this way, adipokines could impact key elements like ovarian follicles, corpus luteum, Leydig cells, and spermatogenesis. Moreover, polymorphisms of adipokines genes have been identified in domestic animals with economic traits. Domestic animal production and reproduction traits are also affected by genetic variability in the adipokine genes. Therefore, this review aims to summarize adipokines and how they are known to regulate reproductive physiology, such as the production of steroid hormones, cell proliferation, oocyte maturation, and sperm development in domestic animals.
Animal production sciences are keenly interested in the development biology of adipose tissue, and over 75 years, important classical research on farm animal adipose tissue accretion has gained traction [1, 2]. Adipose tissue is found throughout the body, including the subcutaneous, retroperitoneal, abdominal, and visceral regions, as well as in proximity to different tissues and organs [3]. The adipose tissue is made up of adipocytes and an extracellular matrix that houses macrophages, primary adipocytes, endothelial cells, and fibroblasts [4]. The two primary types of adipose tissue, white adipose tissue and brown adipose tissue, are composed mostly of white adipocytes and brown adipocytes, respectively [5]. Besides their color differentiation, these tissues differ in terms of their morphology, partitioning, genes, and functions [6]. Adipocytes in brown adipose tissue have small diameters (25–40 mm), are multilocular, contain lipid droplets, and possess large amounts of mitochondria. These cells are responsible for thermogenesis, heat production, and thermal regulation [7]. This type of adipose tissue is present in newborn animals and adult hibernating mammals in most species [7, 8]. In adult animals, white adipose tissue is the primary form, consisting primarily of adipocytes and a stromal vascular fraction which includes macrophages, capillary endothelial cells, undifferentiated preadipocytes, pluripotent stem cells, and fibroblasts [1]. It is intriguing to note that these adipocytes contain a minimal number of mitochondria, as the majority of their cytoplasm is taken up by a single, significant fat vacuole [8]. Besides providing mechanical support and protection for certain parts of the body, this fatty tissue subtype also plays an endocrine role [1, 8]. The third adipocyte type, commonly known as "beige/brite" adipocytes, has been described in cattle and sheep as a response to hormonal stimuli and cold [9].
Mammalian adipose tissue plays a crucial role in converting stored fat into valuable energy, specifically in the form of triacylglycerols (TAGs). This stored energy becomes especially crucial during times of limited energy availability [10]. Previously believed to be just a place for storing lipids, adipose tissue is now acknowledged for its complex involvement in metabolism and endocrine functions [11]. In addition, Sauerwein et al. [12] report that adipose tissue modulates common processes like reproduction, inflammation, and immune response. Adipocytokines and adipokines, or hormones and cytokines secreted by adipose tissue, are collectively called adipocytokines. These include tumor necrosis factor-alpha, interleukin 6, acylation-stimulating protein, leptin, ghrelin, adiponectin, aromatized steroid hormones (plasminogen activator inhibitor-1), and resistin [11, 12, 13]. Adipokines have been shown to play an important role in mammalian reproduction. The ovary has also been shown to serve as a target organ for adipokines. The presence of leptin, chemerin, vaspin, adiponectin, visfatin, and resistin has been confirmed in various ovarian and testicular structures, including the granulosa, theca, luteal cells, seminal plasma, and Leydig cells [14, 15]. According to the studies mentioned above, adipokines link metabolic status with reproduction in most domestic animals. These studies have investigated whether adipokines impact fertility in livestock, either separately or specifically in studies focused on female or male reproduction. Research is conducted on the metabolic and endocrine roles of adipokines’ effects on spermatozoa [14] and metabolic control of livestock ovary functions [16]. The findings regarding adiponectin and leptin, two extensively studied adipokines in mammals, are consistent, confirming their impact on livestock reproduction [13, 14]. In recent years, there has been a growing interest in newly identified adipokine candidates, such as chemerin, visfatin, resistin, and apelin. These candidates are closely associated with obesity and insulin resistance, particularly in humans, but their study in livestock is limited [17]. Consequently, these emerging adipokines may function as metabolic sensors that regulate reproductive processes in response to changes in energy balance. To address this knowledge gap, this review summarizes the effects of adipokines on livestock reproduction, shedding light on the potential significance of adipokines in reproductive processes, thereby contributing to advancements in livestock reproduction. Figure 1 summarizes the adipokines and livestock reproductive performance.
Adipose tissue is not only a repository for lipids but also an endocrine gland that secretes many mediators known as adipokines [18]. These adipokines influence energy metabolism, glucose homeostasis, angiogenesis, and reproduction [1, 19]. Energy metabolism plays a crucial role in ruminant reproduction. Reproduction in ruminants directly affects steroid hormone secretion, which is closely linked with animal energy status [20]. When fatty acids are available in abundance, steroid and eicosanoid secretion is increased, which can cause altered testis, ovarian, and uterine functions and affect pregnancy rates [21]. The impact of fatty acids on gene transcription in cells goes beyond measure, as it triggers the synthesis of vital reproductive proteins [19]. Most species of animals have higher energy requirements during reproductive periods. A high amount of energy is expended during gametogenesis, gestation, and lactation. Males and females often use body reserves as a form of resource storage to fulfill these demands [22]. Maternal fat has a significant influence on reproductive processes and positively impacts litter size and offspring mass in various species, as Michel and Bonnet demonstrated in 2012 [23]. Two studies report a significant alteration in the composition of brown adipocytes in ovine adipose tissue between mid-gender and 1 month of age [9, 24]. In this regard, deficiencies in functional fatty acids in livestock negatively affect their reproductive health. These factors can lead to a delay in puberty onset, loss of sensation, irregular ovulation, and decreased production of vital reproductive hormones, such as gonadotropin-releasing hormone (GnRH) -the hormone that controls the pituitary and ovaries of ruminants, estrogen, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and the hindrance of follicle development [25, 26].
Livestock uses functional fatty acids to regulate various reproductive processes. The significance of functional fatty acids supply for the maturation of oocytes and the development of embryos in livestock has been emphasized by Ye et al. [27]. Recent studies have found that functional fatty acids influence steroidogenesis in granulosa cells/corpus luteum as well as the composition of follicular fluid to improve follicular growth and therefore oocyte quality in livestock [21]. Fatty acid supplementation, especially polyunsaturated fatty acids (PUFA), stimulates follicle development and increases steroid hormone production, which also increases plasma progesterone concentration [26]. Furthermore, fatty acids are metabolized into other molecules, such as cannabinoids, prostaglandins, lysophospholipids, sphingosine 1-phosphate, and steroid hormones, which are important for maintaining reproduction in livestock [21].
Many domestic animals can reproduce in response to adipokines, as shown in the studies above. Most studies on adipokines have focused on leptin and adiponectin, however, chemerin, apelin, resistin, and visfatin have received relatively little attention [4, 17]. Adiponectin and leptin play vital roles in several physiological processes, including reproduction, as described in several studies [1, 4, 17]. Additionally, little research is available about genetic variations in the adipokine family that could contribute to the economic performance of ruminants, including leptin gene polymorphisms and growth traits in native Chinese cattle [28], adiponectin gene polymorphisms and litter size in Awassi sheep [29], and chemerin gene polymorphisms and carcass traits in Japanese black cattle [30]. Therefore, we focused on other adipokines identified and recognized as crucial biomarkers of energy metabolism, such as chemerin, visfatin, resistin, apelin, and their genetic polymorphism.
2.1 LeptinLeptin is a 16-kD protein that is produced mainly in adipose tissue and is involved in regulating body homeostasis, thermogenesis, energy intake, storage, expenditure, immunity, and reproduction [1, 31, 32, 33]. Reproductive function, like other physiological functions, relies on energy stored in adipose tissue, specifically fat [34]. Animals’ body fat mass and body mass index are correlated with plasma leptin concentrations [35]. Leptin is considered a key hormone linking body fat to reproduction since it sends the appropriate signal to inform the reproductive system of metabolic status [32]. The connection between energy reserves and reproductive function has been a subject of interest for a while. A captivating hypothesis proposes that metabolic signals act as the link between adipose stores and neuroendocrine function [36]. There is evidence that leptin influences the central reproductive axis via its receptors and the neurotransmitter neuropeptide Y. Additionally, leptin is known to modulate reproduction at gonadal sites directly [37]. Leptin could also activate both guanylate cyclase and cyclooxygenase-1 in GnRH neurons, which then release GnRH through guanylate cyclase-induced nitric oxide (NO) release [38]. Activation of the NO synthase by leptin stimulates the pituitary to release LH and FSH in gonadotropes [39]. Leptin plays a vital role in the regulation of reproductive performance in ruminants by promoting the release of GnRH, FSH, and LH [38, 40]. Leptin’s impact on reproductive functions has been firmly established, particularly in terms of its role in regulating ovarian function, facilitating oocyte maturation, supporting embryo development, and promoting successful embryo implantation [34]. Moreover, leptin levels in sheep increased during mid-pregnancy and remained high following delivery [38].
Studies conducted on farm animals have shown close relationships between polymorphisms in the leptin gene and reproductive characteristics. Clempson et al. [41] reported a significant link between leptin SNP A1457G and fertility traits in Holstein cows. A dual effect of leptin on sperm exists with positive effects at physiological levels and negative effects at high seminal concentrations [14]. Avondo et al. [42] conducted a study to investigate the impact of variations within intron 1 of the leptin gene (LEP) on milk production, composition, and metabolic status in Girgentana goats. The findings of these studies confirm the importance of LEP polymorphisms in determining milk fatty acid composition in the L genotype. A captivating finding is revealed in a recent study led by Ibrahim et al. [43]. The study shed light on a particular variation, c.670639T/C, found in exon 1 of the caprine leptin gene. This discovery proved to have a significant influence on both milk production and milk protein content in Barki goats. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method is used to detect SNP T93262901C in intron 2 of the leptin gene in Sahiwal cows [44] as a marker of weight at first service, weight at first calving, first service period, and first calving interval. Recently, the study conducted by Nugroho et al. [45] revealed a significant connection between the leptin gene SNP g.1180C>T in exon 2 and various essential traits such as growth, carcass quality, milk production, and reproduction in Madura cattle.
2.2 AdiponectinWhite adipose tissue is the primary source of adiponectin, a hormone that belongs to the adipokine family. Adiponectin has several functions in livestock, among them lipid metabolism, energy regulation, immunity, insulin sensitivity, and ovarian function. Energy metabolism and ovarian function are among its most significant functions [46]. According to Forootan et al. [47], adiponectin regulates fat metabolism and reproduction. Receptor binding is the first step in activation and mechanism of action. There are three receptors for adiponectin, AdipoRI, AdipoRII, and T-cadherin [46]. Considering that Adiponectin RI and RII are possibly present in the pituitary, adiponectin could affect reproductive function by affecting the hypothalamus-pituitary-gonadal axis and/or peripheral behavior in the ovary [16, 47]. Several livestock species, including chickens, cattle, and goats, express both adiponectin and its receptors. Furthermore, it is worth noting that adiponectin receptors can be found in the follicular and luteal cells of farm animals [46]. This implication suggests that these receptors potentially have a significant impact on the reproductive processes [47]. The effects of adiponectin on bovine granulosa cells in vitro have been described by Elis et al. [48]. Sperm parameters appear to be influenced positively by adiponectin. The morphology of the sperm improves when adiponectin levels are increased [14]. The amount of circulating adiponectin in the cow increases during her estrous cycle after ovulation and decreases after the next. Furthermore, high-producing dairy cows with high postpartum adiponectin concentrations start their luteal cycle earlier [49].
It is becoming increasingly clear that animal genetic polymorphism and reproductive pathways are linked. A study by Zhang et al. [50] carried out in 2016 revealed that a new SNP (c.1138G > A) exhibits a positive correlation with litter size in Wannan Black pigs. In Indian Sahiwal cows, the ADIPOQ/TasI genotypes at nucleotide position 1431C>T also resulted in longer calving intervals, longer lactation periods, and higher milk yields than CC or CT genotypes [51]. According to AL-Jaryan et al. [52], a novel mutation of the ADIPOQ gene, c.198473337C > A, affects lipid profiles in Awassi sheep and shows changes in their levels of sex hormones.
2.3 ResistinResistin (RETN) is an essential adipokine produced by adipocytes. A key role it plays is in regulating energy metabolism, affecting insulin sensitivity in peripheral tissues, and thereby influencing immunity and reproduction [53]. There have been numerous studies linking resistin to reproductive function. A research study by Biernat et al. [54] found that resistin influences the secretion of gonadotrophins from the anterior pituitary in sheep. The pituitary is also involved in controlling resistin by secreting gonadotrophins. This suggests that resistin may play a role in the hypothalamic-pituitary axis [55]. Cattle granulosa cell proliferation is enhanced by resistin in larger follicles, whereas it is inhibited by resistin in smaller follicles [16]. The presence of resistin and its increase during follicular development is also observed for the first time in prepubertal pig ovarian follicles. Furthermore, a study in cattle found that resistin affected in vitro steroidogenesis [48]. Resistin stimulates steroidogenesis in ovarian follicles by activating steroidogenic enzymes (CYP11A1, 3betaHSD, CYP17A1, and 17 betaHS) [56]. In addition to modulating steroidogenesis, resistin is also able to regulate cellular proliferation, suggesting it could serve as a metabolic signal controlling reproductive activity [57]. As well as this, both males and females could be affected by resistin’s effects on fertility. Resistin (mRNA and protein) is expressed in several reproductive tissues, such as the hypothalamus, pituitary gland, ovary, and testis [58]. The importance of the above-mentioned resistin in reproduction has been well documented, however, their genetic polymorphism has been little studied. In the study by Pandey et al. [59], two genotypes (AA and AB) are detected in exon-2 of the RETN gene which is associated with reproduction and productivity traits. There is a prevalence of 0.836 for the A allele compared to 0.164 for the B allele. These findings indicate that the A allele could serve as a genetic indicator for choosing Sahiwal cattle with superior reproductive and productive traits. RETN gene polymorphism plays an important role in livestock reproduction, but more research is needed to understand their dynamics.
2.4 VisfatinAdipose tissue secretes Visfatin (52 kDa), also known as nicotinamide phosphoribosyltransferase (NAMPT), which increases during adipogenesis [60]. Various tissues, including bone marrow, liver, muscle, gonads, as well as various other tissues, appear to express this protein and contribute to the regulation of energy metabolism [61]. Juengel et al. [49] and Kaminski et al. [62] have determined that visfatin enhances steroid secretion by granulosa cells through the regulation of GnRH. The expression of visfatin in gonads and its involvement in ovarian steroidogenesis in hen and buffalo granulosa cells is now well established [63, 64]. A large amount of visfatin is expressed in pig ovarian follicles, and its expression is regulated by hormones, such as gonadotropins, insulin, steroids, and prostaglandins. This suggests that visfatin may play a crucial role in regulating porcine ovarian follicular function [60]. Furthermore, spermatocytes, Leydig cells, and spermatozoa contain this protein. Visfatin levels in the seminal plasma are significantly higher than in the blood, indicating a significant and localized production within the male genital tract [14]. However, few studies have been conducted on visfatin polymorphism and its impact on cattle productivity. While there have been a few studies conducted on the subject associated with growth traits in Chinese cattle [65, 66], there is a noticeable lack of research concerning the polymorphism of the visfatin gene and its impact on reproductive characteristics in livestock.
2.5 ChemerinAdipokine chemerin (16 kDa), also known as retinoic acid receptor response protein 2 (RARRES2) or Tazarotene-induced gene 2 (TIG2), is mainly expressed by white adipocytes [67]. The hypothalamus and pituitary glands are also known to express the chemerin system, suggesting an impact on reproductive neuroendocrine processing [68]. The release of gonadotropins from the pituitary gland seems to be influenced by chemerin (circulating or produced locally in the brain) [69]. Oocyte maturation and granulosa cell steroidogenesis are affected by this hormone in dairy cows. A study showed that chemerin blocked meiotic progression at the germinal vesicle stage in cumulus-oocyte complexes and inhibited MAPK3/1 phosphorylation in oocytes and cumulus cells when matured in vitro [70]. Moreover, chemerin has been shown to affect sperm parameters dramatically when its levels are high [14]. According to Gudelska et al. [67], chemerin has a significant impact on the synthesis of progesterone and estradiol by modulating the Erk1/2 and Akt signaling pathways. This suggests that chemerin might play a crucial role in the regulation of steroidogenesis in porcine. Even though the chemerin gene has polymorphisms, there are only a few studies on it. A novel SNP (868A>G in exon 2 and 2692C>T in exon 5) of the chemerin gene has been identified in Qinchuan cattle that is related to carcass and meat quality traits [71]. Japanese Black cattle have a c.276C>T SNP in the chemerin gene affects carcass traits and intramuscular fat composition [30]. However, no studies have been conducted on polymorphisms of the chemerin gene in farm animals and reproductive traits.
2.6 ApelinApelin (APLN) is a newly described adipokine produced mostly by adipose tissue [72]. There is a novel bioactive peptide named APLN that belongs to the adipokine family and binds to a specific G protein-coupled receptor referred to as APLNR [73]. APLN and APLNR are also found in the gonads, supraoptic hypothalamus, and paraventricular hypothalamus, suggesting that they are involved in the control of reproduction [72]. Considering apelin and its receptor are located in reproductive areas like the pituitary gland and hypothalamus, its role in enhancing steroid secretion by granulosa cells, as well as controlling the release of LH and FSH, is obvious [74]. The presence of APLN increases the secretion of progesterone and increases cell proliferation in bovine luteinizing granulosa cells, while it slows down meiotic progression when applied to bovine oocytes in vitro [72]. In addition, studies have shown that APLN has a key role in steroidogenesis and folliculogenesis in ovarian granulosa cells, thereby implying that adipokine enhances reproductive functions in buffalo (Bubalus bubalis) [17, 75]. However, no research on the polymorphism of the APLN gene with productive and reproductive traits has been conducted in farm animals.
Adipokines, which are produced by adipocytes, can interact and communicate with the reproductive system as well as with other peripheral organs. Several adipokines exist in the pituitary-hypothalamus axis that regulate reproductive function. Therefore, adipokines could modulate the secretion of gonadotropins, thereby affecting reproductive function at the central level. Examining the role of adipokines in livestock reproduction holds the potential to enhance fertility and impact various reproduction-related traits. This review highlights the influence of different adipokines on the female reproductive system, but it is noteworthy that adipokines and their receptors are also present in male gonads. Consequently, the process of sperm maturation may be influenced by these adipokines. Leptin, adiponectin, resistin, visfatin, chemerin, and apelin affect the maturation of follicles and oocytes, as well as the steroidogenesis of granulosa cells. Moreover, adiponectin, visfatin, and chemerin play a role in regulating Leydig and Sertoli cell proliferation, spermatogenesis, and steroidogenesis.
