Sedentary lifestyles and dietary changes in recent decades have increased the risk of metabolic disorders such as obesity and diabetes worldwide (1). As a result, more than a third of the world’s population is overweight and obese (2).

Obesity is a common metabolic disorder, which is defined as an abnormally high or excessive accumulation of fat and hence a high body mass index (BMI) (3, 4). The World Health Organization (WHO) defines BMI of ≥ 25 kg/m2 as overweight, ≥ 30 kg/m2 as obese, and ≥ 40 kg/m2 as severely obese (3). A Western diet and reduced physical activity are the primary environmental factors that cause obesity, in addition to genetics (5).

Obesity caused by a high-fat diet (HFD) can increase the risk of cardiovascular diseases and metabolic disorders such as type 2 diabetes mellitus (T2DM) and dyslipidemia (4). Many studies have shown that obesity or diabetes in both genders is associated with reproductive dysfunction and infertility by disrupting the hypothalamic-pituitary-gonadal (HPG) axis, as well as by reducing the number and quality of sperm and oocytes (3).

Adipose tissue, the main site of lipid storage, is involved in the production of adipokines or adipocytokines, such as leptin, adiponectin, resistin, visfatin, and apelin, which play a critical role in the control of glucose and lipid metabolism, insulin sensitivity, energy metabolism, immune system, and neuroendocrine function (6–9).

Apelin is a ligand of the G-protein-coupled receptor (GPCR) and regulates several biological functions in the human and rodents body, including blood pressure, fluid homeostasis, food intake and energy balance, immune response, and neuroendocrine response to stress via its autocrine, paracrine, endocrine, and exocrine effects (10, 11). Apelin is produced by adipose tissue, and many other tissues like the central nervous system, heart, kidneys, lungs, mammary glands, and placenta (12, 13). Moreover, its receptor (APJ) is broadly distributed in the lungs, cardiovascular system, kidney, mammary glands, white adipocytes, central nervous system, paraventricular nuclei, gastric mucosa, testes, and uterus (14, 15).

Of note, apelin plays an important regulatory role in glucose metabolism with its insulin-mimetic effects and lipid metabolism by promoting fuel consumption and reducing fat mass (16). According to previous studies, obesity and T2DM by inducing insulin resistance increase apelin levels (17). Moreover, previous studies indicated that the serum levels of apelin and its receptor gene expression can be influenced by diet (18, 19). Apelin expression is also influenced by nutritional status and its plasma levels decrease with fasting and increase with re-feeding (16).

The role of apelinergic system on the HPG axis has been proven, and apelin has been widely described as an influential factor in controlling reproduction in both genders (20). Due to the presence of apelin and its receptor in reproductive-related areas such as the hypothalamus and pituitary gland, its role in controlling the secretion of LH (luteinizing hormone) and FSH (follicle-stimulating hormone) is understandable (21). Furthermore, apelin is associated with reproductive disorders such as polycystic ovary syndrome (PCOS), endometriosis, and ovarian cancer (22).

This review outlines the current knowledge regarding the role of the apelinergic system in different physiological processes from the periphery to the brain, with an emphasis on the regulation of metabolism and metabolic disorders, namely diabetes and obesity. Moreover, its critical role in the physiology of the HPG axis and the reproductive system of both males and females was discussed.

Obesity can affect female reproductive processes, including ovarian follicular recruitment, oocyte growth and quality, oocyte fertilization, embryonic growth, and evolution and implantation (3). Obese women exhibit lower levels of sex hormone-binding globulin (SHBG) and higher levels of androgens, estrogens, and insulin than those with normal body weight (3, 23, 24). Owing to extensive adipose tissue in obese women and the high activity of aromatase enzyme, a larger amount of androgens is converted into estrogens (25), which in turn through negative feedback on the HPG axis impairs gonadotropin secretion resulting in ovulation dysfunction and irregular menstruation (3, 25).

Obesity also adversely affects the male reproductive system and decreases fertility rates (26, 27) owing to a decrease in sperm concentration, an increase in the number of abnormal sperm, and abnormal sperm motility (28, 29). The results of a meta-analysis showed that for every five units of BMI increase, all sperm parameters, including total sperm count, sperm concentration, and semen volume, declined by 2.4%, 1.3%, and 2.0%, respectively (30).

Maternal obesity and HFD also have adverse effects on the reproductive systems of offspring (18). Epidemiological studies in recent decades show that maternal nutrition during pregnancy has important effects on the offspring’s fertility (31). Maternal nutrition during pregnancy can lead to growth abnormalities and reproductive dysfunctions (32). Our previous study revealed that maternal HFD during pregnancy and lactation markedly decreased the number of primary, secondary, and graafian follicles, while increasing the number of atretic follicles in their offspring (18). HFD has also been shown to increase atretic follicles through up-regulation of ovarian cell cycle inhibitors, expansion of granulosa cells (Gc) apoptosis (33), or modifications of the expression of genes engaged in growth, development, and apoptosis of follicles in the ovary (34).

The International Diabetes Federation estimates that 387 million people have diabetes and this is expected to rise to 592 million by 2035 (35, 36). The most common feature of diabetes is hyperglycemia, which occurs as a result of impaired insulin secretion or insulin action (37). Diabetes has become a major public health concern due to its complications, such as neuropathy, nephropathy, retinopathy, cardiovascular disease, and subfertility and infertility (38).

In recent decades, the link between obesity and T2DM has become well-known, and the main cause of this relationship is insulin resistance (39). Obesity is described by enlarged adipose tissue and dyslipidemia resulting in an excessive non-esterified fatty acids (NEFAs) release and the secretion of several biologically active elements, so-called adipokines, including tumor necrotic factor-α (TNF-α) and interleukin-6 (IL-6), leptin, and adiponectin, from the adipose tissue, ultimately promoting systemic low-grade inflammation or meta-inflammation. Obesity-associated inflammation can impair insulin signaling through serine phosphorylation of insulin receptor substrate-1 (IRS-1) and inhibiting phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, resulting in impaired glucose uptake. Besides, disproportionate FFA delivery to the liver increases the rate of gluconeogenesis, resulting in hyperglycemia. Furthermore, long-term exposure to elevated FFAs and increased hepatic triglyceride and glucose synthesis synergistically cause damage to the β-cells of the pancreas and impair insulin secretion, contributing to the development of insulin resistance and T2DM (40, 41).

Increasing the incidence of diabetes in both genders is a major concern for reproductive health (42). Clinical evidence and animal studies have proven that diabetes disrupts fertility, directly by impairing the function and structure of the gonads or indirectly by affecting the HPG axis (43–45). A low amount of gonadotropin-releasing hormone (GnRH) or a decrease in the sensitivity of the pituitary gland to GnRH is one of the factors related to the HPG axis dysfunction (46). The dopaminergic activity also increases in diabetic patients, which can subsequently inhibit GnRH secretion (46).

In the male reproductive system, diabetes induces structural changes like increased interstitial space, the destruction of germinal epithelium and abnormal pattern of seminiferous tubules (47), impairs glucose metabolism in Sertoli/blood testes barrier, reduces GnRH, gonadotropins, and testosterone levels, and the sensitivity of the pituitary gland to GnRH (46). Besides, diabetes decreases sperm quality and/or function, disrupts spermatogenesis, and results in ejaculatory dysfunction and a decreased libido (2, 47–50). Moreover, diabetes via decreasing serum testosterone and gonadotropins levels impairs the feedback mechanisms in Luteinizing hormone-releasing hormone (LHRH) producing cells (43, 44, 47, 50).

Women with diabetes may experience delayed menstruation and earlier menopause, which can affect fertility (51). Furthermore, the risk of polymenorrhea and amenorrhea significantly are increased in diabetic women compared to healthy women (52, 53). Type 1 diabetes can also reduce ovary size and oocyte quality (54), contribute to mitochondrial dysfunction during meiosis, and cause apoptosis of cumulus cells and DNA methylation (54). Besides, hyperinsulinemia observed in T2DM can change the levels of insulin-like growth factor binding protein (IGFBP), insulin-like growth factor 1 (IGF-1), and SHBG, which in turn cause an increase in androgen secretion from the ovaries and adrenals, and ultimately anovulation (46).

Obesity and overweight are also associated with a clustering of metabolic risk factors in early pregnancy and an increase in the risk of GDM (55). During the second and third trimester, 5-10% of pregnant women experience GDM, which involves hyperglycemia, glucose intolerance, and insulin resistance (56–58). Obesity, inactivity, advanced maternal age, family history of T2DM, GDM in the previous pregnancy and PCOS may cause GDM (59).

GDM has a series of negative effects on the health of the mother and offspring (58). Evidence shows that GDM increases fetal macrosomia and preeclampsia in the short term (58). It is estimated that 70% of women with GDM may develop T2DM later, up to 28 years after delivery (60). Infants born to mothers with GDM are more prone to neonatal hypoglycemia, hyperbilirubinemia, hypocalcemia, respiratory distress syndrome, and polycythemia (61). Moreover, GDM offspring will be at an increased risk of obesity and impaired glucose metabolism during childhood, adolescence, and youth (62).

Of note, diabetes adversely affects the reproductive function of offspring (63, 64). In this regard, offspring born to diabetic dams showed prostate tissue damage, decreased testosterone levels, and decreased sperm count and testicular tissue weight (65). Interestingly, GDM and intrauterine exposure to hyperglycemia predispose offspring to future reproductive dysfunction by altering the expression of genes involved in the differentiation and proliferation of Sertoli cells in the testes like p27kip1, CX43 and aromatase (66).

Apelin is a small endogenous peptide, which interacts with class A G-protein-coupled receptor (GPCR), the APJ receptor. The APLN gene, located on chromosome Xq 25-26, translates to a 77 amino acids prepropeptide or apelin precursor, which is then cleaved into proapelin or apelin-55 through a proteolytic event. Proapelin is further cleaved into different apelin isoforms, based on their length, including apelin 13, 17, and 36. Apelin has a shot half-life (less than 5 min), and its plasma concentration in healthy human and mice is 0.26 ± 0.03 nmol/L and 100–1000 pg/mL, respectively (67). The APJ receptor has varying affinity for different apelin isoforms. Short isoforms like apelin-13 have low affinity and quickly dissociate, whereas longer isoforms (apelin-17 and -36) have high affinity and bind tightly. Since apelin-13 exhibits much stronger biological potency than apelin-36, it is widely used for exploring the physiological effects of apelin in in vitro and in vivo preparations (20). Post-translational modification of apelin-13 produces pyroglutamate [Pry (1)- apelin-13, containing a pyroglutamate group at its N-terminal, which is more resistant to degradation by peptidases and has a longer half-life and represents the major isoform of apelin in human tissues (68). The concentration of apelin isoforms is not the same in different organs. For example, apelin-36 is the most abundant form in the testis, uterus, and lung, and [Pry (1)]-apelin-13 is the dominant isoform in human blood (ranges from 7.7 to 23.3 pg/ml), brain, and heart (69). Moreover, pry¹-apelin-13 and apelin-17 are the predominant forms in the plasma (70, 71).

The apelin receptor (APJ), an intron-less gene and a GPCR, was first identified in 1993. In humans, APJ is encoded by the APLNR gene, presented at chromosome 11q12, and in rats and mice, it is encoded by Aplnr gene, located on the chromosomal locations 3q24 and 2E1, respectively (13). Compared to the rat and mouse APJ, the human’s protein structure of apelin receptors contains 380-amino acid (versus 377-amino acid in rat and mouse APJ) and shares 90% sequence homology with rat and 92% homology with mouse APJ. The endogenous ligands for the APJ receptor exhibit nanomolar affinity, and 13-amino acid in their C-terminal region are essential for receptor binding (72).

Apelin and its receptor are expressed in many peripheral tissues in addition to the central nervous system, including the lungs, cardiovascular system, kidneys, mammary glands, white adipose tissue, gastric mucosa, testis, and uterus (73). In addition, studies in mice revealed that apelin is expressed in the endothelial part of the arterioles in the liver, pancreas, lung, adipose tissue, and spleen (74, 75). Table 1 shows the expression pattern of Apelin/APJ receptor in various tissues and species.

APJ couples to different G-protein subunits, including G_αi/o, G_αs, G_αq/11, and G_α12/13. The APJ receptor couples to G_αi/o G-protein and subsequently inhibits adenylated cyclase and c-AMP production thereby the protein kinase A (PKA) pathway, and activates extracellular-regulated kinases (ERKs) and phosphoinositide 3-kinase (PI3K)/Akt (PKB) signaling, which play a fundamental role in cell proliferation and survival. Conversely, G_αs mediates the activation of adenylyl cyclase, causing PKA production. APJ coupling to Gαq/11 activates the phospholipase C (PLC)/AMP-activated protein kinase (AMPK) pathway, leading to increased intracellular calcium. Furthermore, activation of G_α12/13 results in rearrangement of the cytoskeleton (76). Apelin-13 is a potent Gα_i1 activator and promotes cell proliferation, migration, and survival, and metabolic function via activation of the PI3K/Akt or mitogen-activated protein kinase (MAPK) pathways (77). All bioactive apelin isoforms bind to APJ to couple G_αi and inhibit cAMP production. Both apelin-13 and apelin-36 stimulate APJ coupling to G_αi and G_αq, resulting in the activation of ERK1/2 and PLC signaling pathways (78).

Upon sustained activation of APJ, phosphorylation of APJ receptor by GPCR kinase-β recruits β-arrestin promoting receptor desensitization and internalization (79). The fate of the internalized APJ receptor is ligand-dependent, in which [Pry (1)]-apelin-13 or apelin-13 internalized receptor is rapidly detached from β-arrestin and recycled to the cell membrane, whereas apelin-36 forms a stable binding of β-arrestin to APJ and leads to its degradation by lysosome (80).

Apelin and its receptor are widely distributed in neurons and oligodendrocytes of the different brain regions including the hypothalamus, medulla oblongata, hippocampus, septum, amygdale, forebrain, and brainstem (12), indicating that the apelinergic system plays a major role in neural signaling (73). The protective effect of apelin on cortical neurons can be exerted by inhibiting the production of reactive oxygen species (ROS), the release of cytochrome c from mitochondria into the cytosol, mitochondrial depolarization, and apoptosis via Erk/Akt signaling pathways (81). In a study that examined the effects of apelin-13 on inflammation caused by cerebral ischemia-reperfusion injury in rats, it was shown that treatment with apelin-13 at the beginning of reperfusion decreased the expression of inflammatory mediators such as IL-1β, TNF-α, and intercellular adhesion molecule-1 (ICAM-1) (82). The apelin receptor is also expressed in the corticotrophs in the pituitary gland, where it stimulates the release of ACTH in an autocrine/paracrine way (83).

The action of apelin on the body depends on the dose and route of administration (84). Administration of apelin intracerebroventricularly (i.c.v.) in a dose-dependent manner, increases the secretion of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone, vasopressin, while decreases the secretion of prolactin, thyroid-stimulating hormone (TSH), growth hormone, FSH, and LH (83, 85). It has been shown that blood pressure, nutritional behavior, and the secretion of pituitary hormones can be altered by intraventricular injection of apelin in mice (85).

Apelin is also involved in regulating food consumption and appetite. Apelin suppresses appetite by inducing α-melanocyte-stimulating hormone (α-MSH) release expression in pro-opiomelanocortin (POMC) neurons (86). Taheri et al. reported that intraventricular injection of apelin to fed animals had no significant effect on their food intake; however, apelin administration (at a dose of 30 nmol) in the fasted animals increased food intake at 2-4 h (85).

Previous studies showed that apelin-containing neurons in the hypothalamic nuclei, namely paraventricular (PVN) and supraoptic (SON) project toward the posterior pituitary and release apelin along with vasopressin (VP) and oxytocin into the blood, indicating that apelin affects fluid homeostasis and drinking behavior, but still many inconsistencies exist that remain to be elucidated.

Apelin and APJ receptors are co-localized with VP in magnocellular VP-ergic neurons of the hypothalamus, where apelin inhibits the activity of these neurons and thereby hypothalamic VP release (87, 88). Preclinical and clinical evidence also confirms the reciprocal interaction between apelin and VP. Apelin not only reduces central VP secretion but also opposes the actions of VP on the kidney and inhibits water reabsorption in the renal collecting duct by preventing aquaporin 2 (AQP-2) channels translocation to the apical membrane (89, 90). Roberts et al. also showed that APJ receptor knockout impaired drinking behavior and water hemostasis, exhibited by decreased water intake and failure to concentrate urine in response to exposure to water restriction (91). In contrast, Kubra et al. demonstrated that apelin gene knockout had no effect on water intake in water-deprived mice (92).

In physiological conditions, magnocellular neurons of the hypothalamus balance apelin and VP release to maintain normal plasma osmolality. In healthy individuals, hyperosmolality increases VP and decreases apelin, resulting in water retention, while water loading induces opposite effects (70). Systemic or central apelin injection had different effects on water intake in animals. Some studies found that injecting apelin systemically or centrally in normovolemic animals increased water intake (85, 93), while others found that injecting apelin centrally in animals with HFD-induced obesity or water deprivation decreased water intake and VP plasma levels (94). Mitra et al. discovered that administering apelin centrally or peripherally to animals with free water access did not affect water intake and did not reduce water intake in water-deprived rats (95).

Central injection of apelin-17 to lactating mice attenuated plasma VP levels and increased diuresis (71). One study showed that subcutaneous administration of an apelin-17 stable analog (LIT01-196) in normal water-loading and normonatremic condition promoted aquaretic effects and increased urine output and water intake independent of affecting central VP secretion. Moreover, apelin-17 analog administration in the excessive VP secretion model (syndrome of inappropriate antidiuresis) corrected fluid homeostasis and plasma sodium levels by inhibiting the effect of VP on AQP-2 channels in the collecting duct and increasing water diuresis (96).

Nevertheless, intravenous injection of [Pry (1)]-apelin 13 to hydrated sheep has been shown to increase plasma VP concentration (97). An in vitro study also demonstrated that apelin-13 (100 nmol) stimulated the release of VP from hypothalamic explants. It seems that depending on the dose and isoform of apelin and the conditions of the experiment (physiological or special conditions such as water deprivation, lactation, and hyponatremia, which can change the basal secretion of VP) the effects of apelin on magnocellular VP-ergic neurons can be different (71, 85).

Previous reports support the effects of apelin on the cardiovascular system (98). Administration of apelin has been shown to increase the production of nitric oxide (NO) in the endothelium of blood vessels primarily through the activation of endothelial nitric oxide synthase (eNOS) and thus decreases blood pressure (74). Furthermore, apelin exerts an antioxidant effect in the cardiomyocytes, vessels, and adipocytes by suppressing the release of reactive oxygen species (ROS) and enhancing the expression of antioxidant enzymes (99, 100). The apelinergic system also stimulates gastric and endothelial cell proliferation, regulates catecholamine-mediated lipolysis, increases glucose uptake in insulin-sensitive tissues, promotes retinal angiogenesis, acts as a positive inotrope, and maintains fluid homeostasis (16, 101). Apelin activates Na+/H+ and Na+/Ca2+ exchangers and inositol triphosphate receptors, causing calcium release from the sarcoplasmic reticulum and increasing myocardial contraction (68, 102, 103).

The apelinergic system is an essential regulator of energy metabolism and exerts diverse beneficial effects against the development of the metabolic disorders, particularly diabetes and obesity. Apelin also regulates fertility and reproductive functions in physiological and pathological conditions through its autocrine and/or paracrine effects. Therefore, targeting this pathway is a current demand and a novel outlook that could provide more treatment options for improving reproductive capacity in metabolic disorders. More detailed studies are required to address all roles of the apelinergic system in this context.

KM and ZZ wrote the first draft of the manuscript. FF conceived and designed the study. FF, GH, and SN reviewed and edited the manuscript. All authors read and approved the final version of the manuscript.