Abstract
In brief
Maternal obesity impairs uterine function, compromising embryo implantation and pregnancy establishment, posing also long-term risks to offspring health. We explore the contribution of impaired decidualisation to failed embryo implantation and placentation in obese mothers, highlighting the role of altered uterine leptin signalling in the dysregulation of extracellular matrix remodelling, vascularisation and cell proliferation and differentiation.
Abstract
Obesity drastically affects maternal health and reproductive outcomes, being often associated with endocrine imbalance, compromised ovarian function and pregnancy complications. The plastic nature of pregnancy may render the developing foetus particularly vulnerable to oscillations in maternal metabolism, ultimately shaping the health trajectories of the offspring. Presently, we discuss the effect of maternal obesity on decidualisation, a critical step for embryo implantation and placental development. Decidualisation encompasses the differentiation of endometrial stromal cells into specialised decidua. Impaired decidualisation was linked to pregnancy complications, and recent studies suggest that maternal obesity has a detrimental effect on decidualisation. Leptin, an adipokine significantly increased in the circulation of obese women, is known to regulate endometrial function and decidualisation, modulating immune response, angiogenesis and cell proliferation. Furthermore, hyperleptinaemia in obese mothers was linked to altered leptin signalling in the uterus and compromised endometrial function. In this review, we explore the underlying molecular mechanisms linking altered uterine leptin signalling to impaired decidualisation and early pregnancy complications in obese mothers.
Introduction
Obesity is a major societal concern, placing a significant financial burden on healthcare systems because of the treatment of obesity-related diseases, such as type 2 diabetes, cardiovascular disease and cancer (Zhang et al. 2023). The World Health Organization (WHO) recently reported that global obesity has nearly doubled over the past 30 years (World Health Organization 2016). In 2022, approximately 16% of the adults aged 18 and older were obese and 43% were overweight (World Health Organization 2016). These concerning findings are particularly significant among women of reproductive age, with 50% of pregnancies occurring in either overweight or obese women (Kent et al. 2024). Maternal obesity profoundly affects the reproductive performance (Zheng et al. 2024). The endocrine imbalance observed in obese mothers frequently leads to compromised ovarian function, decreased oocyte quality, pregnancy complications and infertility (Wołodko et al. 2021). Furthermore, the foetus is particularly vulnerable to changes in maternal physiology throughout pregnancy, which can affect both embryo development and the health trajectories of offspring (Dearden & Ozanne 2023). The Developmental Origins of Health and Disease (DOHaD) hypothesis postulates that the occurrence of adverse environmental cues during the first 1000 days of life can predispose to chronic disease later in life (Oestreich & Moley 2017). Deciphering the effects of maternal obesity on decidualisation and pregnancy establishment is crucial to improving fertility, ensuring better health trajectories for the next generation.
A successful pregnancy commences with the implantation of the embryo, which relies on the complex interplay between the blastocyst and the receptive endometrium. Crucially, this series of events is preceded by the decidualisation of the endometrium (Ng et al. 2020a). Orchestrated by oestradiol (E2) and progesterone (P4), decidualisation comprises the differentiation of endometrial stromal fibroblasts into decidual cells. These specialised polyploid cells exhibit secretory properties that nourish the embryo in the uterine cavity until implantation (Ramathal et al. 2010). Therefore, defects in decidualisation and endometrial remodelling can compromise implantation and the development of the placenta, ultimately leading to pregnancy disorders (Rhee et al. 2016). In summary, decidualisation is key to embryo implantation and pregnancy establishment.
Recent research on mouse models of maternal obesity has revealed the association between the expansion of the adipose tissue and compromised decidualisation and pregnancy complications (Rhee et al. 2016, Saben et al. 2016). Leptin, a hormone primarily secreted by the adipose tissue, was shown to be significantly elevated in the plasma of obese mothers (Pérez-Pérez et al. 2018). Furthermore, leptin is also known to regulate the decidualisation of the endometrium (Walewska et al. 2024), controlling immune response, angiogenesis and cell proliferation (La Cava 2017, Liu et al. 2011, Tahergorabi & Khazaei 2015). This review explores the effect of altered uterine leptin signalling on the pathogenesis of impaired decidualisation and early pregnancy complications in obese mothers, offering insight into putative mechanisms for future therapeutic strategies.
Obesity and pregnancy
Obesity has become a major global crisis, with a dramatic increase over the past century. By the end of 2030, it is expected that obesity will affect nearly 45–50% of the global population (World Obesity Federation 2024). The World Obesity Federation describes obesity as a chronic progressive disease, associated with several comorbidities, spanning from cardiovascular disease and diabetes to various types of cancer (Potdar & Iyasere 2023). Obesity can affect the maternal reproductive health at multiple levels, including decreased oocyte quality or compromised endometrial receptivity and embryo implantation (Silvestris et al. 2018). Furthermore, the literature describes the association between maternal obesity and an increased risk of pregnancy complications such as pre-eclampsia, gestational diabetes mellitus (GDM), macrosomia or foetal growth restriction (FGR) and preterm birth (Lewandowska 2021). Most importantly, maternal obesity has been associated with long-term health consequences for both the mother and her offspring (Wanaditya et al. 2023). Studies documented an increased prevalence of childhood obesity, insulin resistance, type 2 diabetes and cardiovascular disease during adulthood in the offspring of obese mothers (Dearden & Ozanne 2023, Wanaditya et al. 2023). In summary, the growing obesity epidemic poses a significant threat not only to maternal fertility but also to the long-term health of the offspring.
The ‘implantation window’ represents a key phase in early pregnancy, during which the embryo successfully implants in the uterine wall. During this brief period, decidualisation prepares the cyclic endometrium for embryo implantation. Endometrial stromal cells differentiate and originate the decidua, which in association with other parts of the uterine epithelium, establish the foeto–maternal interface, essential for pregnancy (Ramathal et al. 2010, Ng et al. 2020a). Research describes the occurrence of lipotoxicity and increased inflammation and oxidative stress in the endometrium of obese women and animal models of maternal obesity (Sessions-Bresnahan et al. 2018, Bazzano et al. 2021, Gao et al. 2021). In diet-induced obesity (DIO) mice, a reduced number of implantation sites was observed (Rhee et al. 2016, Chen et al. 2023). Furthermore, in vitro studies with endometrial stromal cells from obese women showed diminished responsiveness to the hormonal treatment and compromised decidualisation (Rhee et al. 2016). Overall, altered endometrial function and impaired decidualisation affect embryo implantation in obese mothers, leading to a decreased pregnancy rate and reproductive performance.
The adipose tissue has emerged as a major endocrine organ responsible for the secretion of adipokines. Key players such as leptin, adiponectin, resistin and visfatin are involved in the regulation of important physiological processes including metabolism, energy balance and inflammatory response (Zorena et al. 2020). Leptin is an adipokine extensively studied not only in the context of adipose tissue biology (Zhang & Scarpace 2006) and regulation of food intake (Ardid-ruiz et al. 2016) but also for its role in the regulation of the reproductive tract. Leptin may affect reproductive function, acting centrally at the hypothalamic level or peripherally in the ovaries, endometrium and placenta (Masuzaki et al. 1997, Iwakura et al. 2016, Wołodko et al. 2021, Kabbani et al. 2023). In obese women, increased circulating levels of leptin (Kabbani et al. 2023) were associated with altered leptin activity at the uterine level and an increased risk of pregnancy complications such as abnormal placental development, inadequate trophoblast invasion, pre-eclampsia and FGR (Pérez-Pérez et al. 2018, de Knegt et al. 2021). Understanding the molecular mechanisms underlying the detrimental effect of altered endometrial leptin signalling during decidualisation and implantation will reveal the causes of pregnancy complications in obese mothers.
Leptin and pregnancy
During pregnancy, maternal metabolism drastically changes in order to support both foetal growth and the ever-increasing energy demands from the mother (Hadden & McLaughlin 2009). The maternal body undergoes significant physiological changes including the development of the mammary gland and the accumulation of fat (Khant Aung et al. 2020). Thus, pregnancy is accompanied by a dramatic endocrine shift in the secretion and activity of metabolic hormones such as leptin (Castillo-Castrejon & Powell 2017, Pérez-Pérez et al. 2018). Leptin is known to play a key role in the mobilisation of resources, adjusting maternal metabolism to the increased energy demands of pregnancy (Weihua et al. 2000). Moreover, such metabolic adaptation provides optimal conditions for foetal development (Reitman et al. 2001). Increased levels of maternal leptin during pregnancy have been observed across animal species. In mice, circulating leptin levels rise during mid-gestation (Tomimatsu et al. 1997); conversely, in humans, maternal plasma leptin levels double during the first trimester of pregnancy, returning to pregestational levels shortly after labour (Stefaniak et al. 2019). Increased circulating leptin during pregnancy results from the following: i) augmented leptin secretion from the adipose tissue because of fat mass expansion and enhanced secretion per unit of adipose tissue; ii) placental leptin secretion, notably by the trophoblast cells (Masuzaki et al. 1997) and iii) decreased clearance of leptin from the bloodstream (Henson & Castracane 2000). Leptin production and secretion by the adipose tissue are increased in response to weight gain and fat deposition in the mother, starting in the late second trimester. In addition, leptin produced by the placenta accounts for approximately 15% of the total leptin in the maternal serum (Linnemann et al. 2000). Consequently, leptin emerges as a pivotal hormone governing the endocrine shift during pregnancy, regulating both maternal and foetal metabolism (Anim-Nyame et al. 2000).
The simultaneous increase in leptin plasma levels and food intake during pregnancy often leads to the establishment of leptin resistance or decreased sensitivity to leptin (Khant Aung et al. 2020). Central leptin resistance emerges to promote nutrient availability for the developing foetus and is likely to be induced by the hormonal fluctuations occurring in early pregnancy, such as the elevated circulating levels of P4, prolactin (PRL) and placental lactogen (Gustafson et al. 2019). Such endocrine adaptation in rodents begins well before the increase in maternal energy needs (Clarke et al. 2024). This adaptive response underscores the intricate interplay between the hormonal shift and nutritional requirements in early pregnancy, which become particularly significant in the context of maternal obesity. Hence, pregnancy in obese mothers can lead to excessive circulating levels of leptin and changes in its activity (Gavrilova et al. 1997). Research from our group described the dysregulation of leptin signalling in various components of the reproductive tract from obese mice, such as in ovaries and cumulus cells isolated from pre-ovulatory follicles (Arias-Álvarez et al. 2010, Wołodko et al. 2020) and in the endometrium and decidua (Walewska et al. 2024). Furthermore, other groups evidenced the expression of leptin or its receptors also in ovarian cells and oocytes from human (Löffler et al. 2001) or mouse trophoblast cells (Wang et al. 2014). In conclusion, leptin plays a central role in both metabolic and endocrine adaptations in the mother during early pregnancy, fundamental for foetal development. However, the onset of leptin resistance in the context of maternal obesity can disrupt this important physiological transition because of changes in leptin activity both systemically and within the reproductive tract.
Leptin signalling and leptin receptor activation
Mature leptin consists of a 16 kDa protein that belongs to the class I cytokine family, sharing structural features with interleukin-6 (IL 6) or granulocyte colony-stimulating factor (G-CFS) (Rock et al. 1996). Generally, circulating leptin correlates with the nutritional status and levels of adiposity (Saladin et al. 1995). Nonetheless, other factors such as gender, age, stress and physical activity can affect circulating leptin levels (Ostlund et al. 1996, Landt et al. 1997, Kasacka et al. 2019, Bouillon-Minois et al. 2021). Notably, circulating levels of leptin were reported to be typically higher in females than males, a feature attributed to the opposing effects of testosterone and E2 on leptin production, as well as the greater amount of adipose tissue in females (Li et al. 2022). Given the regulatory role of leptin on reproductive and metabolic function, increased leptin signalling in females suggests that maternal obesity may negatively affect female reproductive health and pregnancy outcomes.
At the cellular level, leptin exerts its effects through six different receptors (OB-Ra–f), which vary in the length of their intracellular domains (Myers 2004a). Various ObR isoforms are produced by alternative splicing from the db gene (Gorska et al. 2010). The receptor isoforms include four short forms (OB-Ra, OB-Rc, OB-Rd and OB-Rf), one long form with intracellular domain (OB-Rb) and one soluble form (OB-Re). OB-Rb signals through four conserved tyrosine residues (Y974, Y985, Y1077 and Y1138) (Gorska et al. 2010) and is activated after tyrosine kinase phosphorylation by Jak family (JAK) 2. Subsequently, OB-Rb activates several signalling pathways including the Janus kinase (JAK)/signalling transducer and activator of transcription (STAT), mitogen-activated protein kinases (MAPK), phosphatidylinositol 3-kinase/protein kinase B/forkhead box O 1 (PI3K-AKT-FOXO1) and AMP-activated protein kinase (AMPK) pathways, among others (Myers 2004b). Phosphorylated Y985 recruits Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2), which triggers the extracellular signal-regulated kinase (ERK) signalling cascade (Xu et al. 2018). Conversely, the phosphorylation of Y1077 and Y1138 recruits the STAT5 and STAT3 respectively, enabling their translocation to the nucleus for gene expression regulation (Myers et al. 2008). The Y1138-STAT3 signalling pathway activates the expression of the suppressor of cytokine signalling 3 (SOCS3), known to bind to Y985, attenuating ObRb signalling through negative feedback (Fig. 1) (Myers et al. 2008). Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) and protein tyrosine phosphatase 1B (PTP1B) are responsible for dephosphorylating JAK2, modulating also OB-Rb signalling (Picardi et al. 2010, Loh et al. 2011). Additionally, OB-Rb has been shown to activate Rho kinase 1 (Frehner et al. 2021), AMPK (Maymó et al. 2010), insulin receptor substrate (IRS) 2 (Do Carmo et al. 2016) and SH2B1 (Rui 2014). The inhibition of leptin signalling through the upregulation of the negative modulators SOCS3, PTPN2 and PTP1B may lead to the establishment of leptin resistance, rendering the signalling pathway inactive (Myers et al. 2008). In summary, leptin signalling is intricately regulated by multiple modulators that control the activation of conserved pathways, such as JAK/STAT, MAPK and AMPK, which are crucial regulators of various cellular functions.
Endometrial function and decidualisation: the role of leptin
The critical role of endometrial decidualisation in embryo implantation and placental development
Successful pregnancy depends not only on the attachment of the embryo to the endometrium but also on the synchronous preparation of the uterine cavity for implantation (Cha et al. 2012). Profound structural, cellular and molecular changes occur in the endometrium throughout cyclicity, leading to the formation of the decidua in species with invasive placentation, such as rodents and humans (Ramathal et al. 2010). In rodents, decidualisation is initiated by the presence of an implanting embryo. The blastocyst enters the uterine cavity four days after fertilisation, communicating with the luminal epithelial cells of the endometrium (Elmore et al. 2022). This initial contact triggers the differentiation of endometrial stromal cells into decidual cells, which transition from a fibroblast-like to an epithelioid-like appearance. Conversely, in humans, the pre-decidualisation of endometrial cells is initiated during the secretory phase of the menstrual cycle, following ovulation (around day 23) (Murata et al. 2022). The differentiation of decidual cells is promoted around the spiral arterioles and capillaries of the superficial layer of the endometrium, regardless of the presence of an embryo (Gellersen et al. 2007). Importantly, pre-decidualisation in women is known to prepare the endometrium for implantation. This process mirrors the proliferation of stromal cells and the activation of decidualisation genes, observed in the mouse endometrium just before embryo implantation (Ramathal et al. 2010). Functionally, the decidua plays a major role in early pregnancy and placental development, protecting the foetus from the maternal immune response, regulating trophoblast invasion and preventing excessive trophoblast expansion within the uterus (Zhang & Wei 2021). Furthermore, the decidua orchestrates the reorganisation of the uterine vascular bed (Woods et al. 2018), modulating local angiogenesis and vasculogenesis. Overall, the decidua is essential for pregnancy establishment, mediating the uterine adaptations necessary for embryo implantation and the development of the placenta (Fig. 2).
Regulation of endometrial function and decidualisation: the interplay between steroid hormones and leptin signalling
Decidualisation is predominantly regulated by the steroid hormones E2 (Shao et al. 2013) and P4 (Large & DeMayo 2012), known to mediate the proliferation, differentiation and polyploidisation of uterine stromal cells (Ng et al. 2020b). In mice, the pre-ovulatory E2 surge induces the proliferation of endometrial stromal cells (Ramathal et al. 2010). Molecularly, E2 activates its nuclear receptors oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERβ), both known to be expressed in endometrial stromal cells (Tan et al. 1999). While ERα plays a major role in cell proliferation and differentiation, ERβ modulates PR expression levels in the luminal epithelium (Weihua et al. 2000). Additionally, ERβ can modulate Erα activation (Curtis et al. 1999). After ovulation, the newly formed corpus luteum produces P4, which terminates the proliferation of the endometrium (proliferative phase), inhibiting mitotic division and promoting cell differentiation. P4 was also shown to regulate secretory activity in both endometrial stromal and epithelial cells, through the activation of the nuclear progesterone receptors PR α and PRβ. Notably, the deletion of PRα in mice resulted in compromised decidualisation, in contrast to PRβ deletion (Conneely & Lydon 2000). In conclusion, decidualisation is primarily initiated by E2 and P4, which control the proliferation and differentiation of endometrial stromal cells.
Beyond the activity of ovarian steroids, other factors are known to regulate endometrial function and decidualisation (Styer et al. 2004). The expression of leptin and its receptor OB-Rb was shown to be increased in endometrial stromal and epithelial cells collected from women in the luteal phase of the oestrous cycle (González et al. 2000). Additionally, plasma levels of leptin were shown to be increased in women during the luteal phase, which temporally coincides with the time of decidualisation (Salem 2021). In vitro studies revealed that the treatment of human endometrial explants with E2 in association with P4, decreased the mRNA transcription of ObRb (Koshiba et al. 2001) but mediated the phosphorylation of STAT3 (Koshiba et al. 2001) and the proliferation of stromal cells (Styer et al. 2004). Immunologically, leptin was shown to modulate the expression of IL6 and other chemokines in the human endometrium (Fukuda et al. 2003). Moreover, recent research showed enhanced self-renewal capacity of human endometrial mesenchymal stromal/stem cells (eMSCs) that presented an increased expression of the leptin receptor (LepR+), pointing to the putative role of leptin in the maintenance of the endometrial epithelium (Fang et al. 2023). Interestingly, leptin signalling in the human endometrium was shown to be modulated by the implanting embryo. A study by González et al. (2000) described the upregulation of OB-Rb in endometrial explants that were cocultured with pre-implantation embryos in vitro (González et al. 2000). These findings collectively underscore the role of leptin in the regulation of endometrial function and decidualisation.
Maternal obesity leads to increased leptin signalling in the endometrium (Walewska et al. 2024). Research on humans showed that elevated leptin levels in the endometrium prior to conception were linked to adverse pregnancy outcomes, such as GDM (Peltokorpi et al. 2022). In patients with endometriosis, leptin was shown to stimulate the growth of epithelial cells through JAK2/STAT3 and ERK pathways (Oh et al. 2013). Finally, the metabolic dysregulation mediated by excessive leptin activity in the endometrium can compromise the molecular and cellular mechanisms controlling decidualisation (Galio et al. 2023). In conclusion, maternal obesity-induced elevated leptin activity in the endometrium may impair decidualisation, increasing the risk of adverse pregnancy outcomes.
Cell cycle regulation during decidualisation: the role of leptin signalling
During decidualisation, increased protein synthesis is known to sustain endometrial stromal cell proliferation, differentiation and polyploidisation, supporting embryo implantation and development (Ramathal et al. 2010). Polyploid decidual cells are specialised cells, which transitioned from a typical mitotic cycle to an endoreduplication cycle (Das 2009), with DNA replication without cell division (Shu et al. 2018). In mice, polyploid decidual cells may present large nuclei with four to eight times more DNA than a regular somatic cell (Das 2009). Concerning cell cycle regulation, G1/S and G2/M are two crucial stages for polyploidy development, mostly controlled by the activity of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) (Das 2009). The crosstalk between cyclin D3, p21 and CDK6 is crucial for the development of polyploidy in stromal cells, throughout decidualisation (Tan et al. 2002). Furthermore, the coordinated expression and interaction between cyclin D3 and CDK4 was shown to promote cell proliferation. Several factors control the expression and activity of cyclins, CDKs and CKIs, thereby influencing the proliferation and differentiation of endometrial stromal cells (Zhu et al. 2014). For instance, under the effects of P4, homeobox A10 (Hoxa10) was shown to facilitate the shift in the expression of the cell cycle regulator CDK4 to CDK6, known to mediate cell cycle progression (Robles et al. 2017). The absence of Hoxa10 expression resulted in the arrest of endometrial stromal cells at the G2/M phase (Lu et al. 2008). Overall, the cell cycle is tightly controlled by CDK proteins, which facilitate the proliferation and decidualisation of endometrial stromal cells.
Leptin is known to regulate the cell cycle, controlling cell proliferation and differentiation. Our recent work revealed that the in vitro treatment of mouse endometrial stromal cells with leptin decreased the mRNA transcription of Hoxa10 (Walewska et al. 2024), suggesting disrupted progression of the cell cycle. Moreover, studies performed in endometrial cancer cells revealed that leptin treatment reduced the number of cells at the G0/G1 phase, increasing the prevalence of cells at the S phase and the expression of cyclin D1 (Catalano et al. 2009). Furthermore, a report on ovarian cancer cells showed also the supportive effects of leptin on cyclin D1 protein expression and the progression of the cell cycle from the G1 to S phase (Ptak et al. 2013). Finally, a single-cell RNA (scRNA-seq) study on human eMSCs reported increased transcription of ObR in cells at the G1 phase, suggesting the involvement of leptin in the activation of the stem cell niche in the endometrial stroma (Fang et al. 2023). In summary, leptin emerges as a key regulator of the cell cycle, controlling the proliferation and differentiation of endometrial stromal cells. Thus, increased leptin signalling in obese mothers may compromise decidualisation and embryo implantation.
Extracellular matrix (ECM) remodelling during decidualisation: the role of leptin signalling
The growth and differentiation of fibroblast-like endometrial cells into decidual cells are associated with significant remodelling and the reduction of the extracellular space. The mouse endometrium can be morphologically compartmentalised into two zones: i) the structural zone or the deep stroma (DS) and ii) the functional zone or the superficial stroma (SS). These areas correspond to the basal and functional layers of the human endometrium respectively (Zhao et al. 2020). Both areas comprise cells with different morphology, metabolism and gene expression profiles (Favaro et al. 2014). The round fibroblasts located near the lumen in the SS play an active role in decidualisation compared with the flattened fibroblasts in the DS, close to the myometrium (Favaro et al. 2014). Their morphology and responsiveness to ovarian steroids is linked to differences in the composition of the extracellular matrix (ECM) (Lu et al. 2011). In mice, collagen I is largely abundant in the nondecidualised stroma of the endometrium, between the implantation sites (Spiess et al. 2007). Conversely, collagen III and V accumulate in the basement membrane, close to the endometrial glands and vessels within the interimplantation areas. During decidualisation, collagen type III can be detected in the ECM surrounding the decidual cells near the implanting embryo (Shi et al. 2020). To promote embryonic attachment and invasion, decidual cells secrete various proteins such as laminin, fibronectin, collagens and heparan sulphate around the endometrial glands (Kirn-Safran et al. 2008, Yin et al. 2018). The secretion of integrins by the decidua enhances cytoskeletal remodelling and focal adhesion, stabilising embryo apposition to the endometrium (Bijovsky et al. 1992). Therefore, ECM remodelling during decidualisation provides structural support for embryo implantation (Lee et al. 2013, Favaro et al. 2014, Liu et al. 2022).
Maternal obesity and the associated increased uterine leptin signalling can compromise ECM remodelling during decidualisation (Castellucci et al. 2000). Studies in cells isolated from uterine leiomyomas in women following hysterectomy revealed that leptin can promote ECM deposition through the activation of JAK2/STAT3 and MAPK/ERK pathways (Reschke et al. 2022). Moreover, the treatment of the cells with the JAK2/STAT3 inhibitor attenuated ECM deposition, while treatment with the MAPK/ERK inhibitor significantly decreased the stimulatory effects of leptin on cell proliferation and ECM deposition (Reschke et al. 2022). These findings may partly explain the increased incidence of uterine leiomyoma in obese women (Reschke et al. 2022). Furthermore, research also demonstrated the supportive actions of leptin on collagen synthesis and deposition in the liver, kidneys or heart (Liu et al. 2022). In hepatic cells, leptin was shown to mediate fibrosis through the production of type I collagen via PI3K/AKT signalling pathway (Niu et al. 2007). Similarly, in kidney mesangial cells, leptin enhanced the synthesis of type I collagen through PI3K-dependent activity (Han et al. 2001). Furthermore, research on human endometrial cells demonstrated that leptin promotes the migration and invasion of epithelial and stromal cells through the upregulation of matrix metalloproteinase - 2 (MMP-2), a major ECM component (Ahn et al. 2015). Additionally, research on pigs revealed that leptin treatment upregulated the mRNA expression of ECM components involved in endometrial receptivity, such as β3-integrin, Mmp9, heparin-binding EGF-like growth factor (Hbegf) and interleukin-1 beta (Il 1β) (Wang et al. 2020). Overall, leptin signalling is a key regulator of ECM remodelling during decidualisation, with significant implications for obesity. Elevated leptin in obesity can disrupt normal ECM dynamics, promoting excessive ECM deposition and cell proliferation.
Endometrial vascular bed remodelling during decidualisation: The role of leptin signalling
During early pregnancy, the uterine vasculature undergoes reorganisation, leading to decreased uterine vascular resistance and increased vascular permeability (Mori et al. 2016). The growth and development of decidual capillaries and arterioles occur through a process known as angiogenesis, which involves the formation and expansion of new blood vessels from pre-existing vasculature (Plaisier 2011). Angiogenesis is primarily regulated by the combined action of proangiogenic cytokines, low levels of oxygen and extensive tissue remodelling (Plaisier 2011). The ovarian hormones E2 and P4, along with vascular endothelial growth factor (VEGF), angiopoietins and uterine natural killer cells, play a critical role in the modulation of angiogenesis in the pregnant uterus (Massri et al. 2023). The first stage of vascular remodelling occurs during early pregnancy and is mainly controlled by the decidua (or trophoblast-independent). The second stage takes place during mid-gestation in mice (gestation days 10.5–11), is trophoblast-dependent and leads to the full development of the placenta. Importantly, the precise regulation of angiogenesis and vasculogenesis in the decidua is crucial for the establishment of the placental vasculature. The imbalance between pro- and anti-angiogenic factors can impair placental development, increasing the risk of pregnancy-related disorders or early miscarriage (Zeng et al. 2023).
Maternal obesity significantly impacts uterine vascularisation during decidualisation and placentation (St-Germain et al. 2020). Previous studies revealed the link between a high body mass index in early pregnancy and lower levels of angiogenic mediators such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor, increasing the risk of pre-eclampsia (Beck et al. 2021, 2022). A recent RNA sequencing analysis conducted by our group on mouse endometrial stromal cells decidualised in vitro demonstrated that the transcription of Flt-1 was decreased in obese mice (Walewska et al. 2024). Importantly, FLT-1, also known as VEGF receptor 1(VEGFR-1), plays a pivotal role in decidual and placental vascularisation (Plaisier et al. 2008). Furthermore, results from our laboratory show altered platelet endothelial cell adhesion molecule (CD31) staining in the decidua of obese mice at E6.5, suggesting delayed decidual vascularisation (Fig. 3A). Finally, we also observed reduced labyrinthine vascularisation in E18.5 placentas collected from obese mice (Fig. 3B). In conclusion, maternal obesity in mice disrupts uterine and placental vascularisation during early pregnancy and placentation, leading to increased risk of pregnancy-related complications (Fig. 4).
Obesity is largely associated with inflammation and the infiltration of immune cells, known to play a significant role in the regulation of vascularisation (Baltayeva et al. 2019). Immune cells, particularly uterine natural killer (uNK) cells, were shown to be abundant in the basalis of deciduas from early pregnancy in mice (Croy et al. 2003). The uNK-cell population can secrete proangiogenic factors such as VEGF-A, which regulates angiogenesis, vascular remodelling and trophoblast endovascular invasion into the uterine vasculature (Lima et al. 2014). Studies in DIO mice demonstrated that altered decidual vascularisation was associated with decreased NK-cell activity (Baltayeva et al. 2019). Obesity was also shown to influence placental angiogenesis and vascularisation, possibly through the downregulation of pathways such as SIRTUIN1/peroxisome proliferator-activated receptor-γ coactivator-1α (SIRT1/PGC-1α) (Peng et al. 2022). Finally, maternal obesity leads to increased placental oxidative stress and decreased placental angiogenesis, through the upregulation of NADPH oxidase 2 (NOX2) (Hu et al. 2019). These findings collectively highlight the detrimental effects of obesity on both decidual and placental angiogenesis.
Leptin is known to be expressed in endothelial cells across multiple organs, playing a regulatory role in angiogenesis (Lijnen 2008). Studies in leptin-deficient mice (ob/ob) revealed the link between leptin and neovasculogenesis, as ob mice presented deficient vascular fenestration in the adipose tissue (Cao et al. 2001). Studies on human endothelial cell lines revealed the effects of leptin on cell proliferation and differentiation, through the activation of AKT and WNT signalling pathways (Yu et al. 2019). Furthermore, leptin was shown to regulate vascularisation through the phosphorylation of VEGFR-2 and subsequent activation of p38MAPK and AKT, which resulted in the stimulation of cyclooxygenase -2 (COX-2) mediated angiogenesis and endothelial cell proliferation (Garonna et al. 2011). Nonetheless, excessive levels of leptin in obese mothers may dysregulate the tight crosstalk between angiogenesis and immune response during decidualisation (Sánchez-Jiménez et al. 2019). Research on endometrial cancer cells showed that leptin regulates the expression of VEGF, IL 1β and leukaemia inhibitory factor in a dose-dependent manner (Carino et al. 2008). Furthermore, increased leptin levels in obese mothers were associated with chronic low-grade inflammation (Iikuni et al. 2008). As a result, augmented leptin signalling in the endometrium of obese mothers compromised cytokine production and immune-mediated response during decidualisation and the associated neovascularisation (Francisco et al. 2018, Faulkner et al. 2022). Notably, leptin can affect the crosstalk between P4 and VEGF (Cao et al. 2001, Salmasi et al. 2021). Elevated leptin levels might also induce oxidative stress within the decidual tissue, disrupting angiogenesis and leading to vascular defects (Zeng et al. 2023). Further research is needed to elucidate the role of leptin in angiogenesis dysregulation during decidualisation, potentially providing new treatment opportunities for obesity-related reproductive complications and infertility.
The contribution of adipokines beyond leptin for decidualisation and early pregnancy establishment
During maternal obesity, altered secretion of adipokines such as adiponectin (ADIPOQ), chemerin, apelin or retinol-binding protein 4 (RBP4) can impact endometrial function, decidualisation and pregnancy establishment (Dawid et al. 2024). The expression of Adipoq mRNA and its receptors AdipoR1 and AdipoR2 was previously shown in mouse decidua during embryo implantation (Kim et al. 2011). Furthermore, the ADIPOQ-established role in ovarian steroidogenesis may also impact endometrial function, particularly through the modulation of the inflammatory response and cell proliferation (Sarankhuu et al. 2024, Zhao et al. 2024). Conversely, the protein levels of another adipokine, chemerin, were shown to be upregulated in porcine endometrium at the time of embryo implantation (Gudelska et al. 2020, Orzechowska et al. 2022). In women, the upregulation of chemerin expression in stromal cells undergoing decidualisation was shown to contribute to endometrial receptivity and embryo implantation, through AMPKα activity (Shen et al. 2013). Finally, reports described that chemerin mediates vascular remodelling and angiogenesis in mouse endometrium during early pregnancy (Zhang et al. 2022). Conversely, apelin, an adipokine known to regulate cell proliferation (Mlyczyńska et al. 2020) and angiogenesis (Helker et al. 2020), was shown to support endometrial receptivity and embryo implantation (Różycka et al. 2018). RNA-seq analysis performed on porcine endometrium treated with apelin revealed the upregulation of genes associated with ECM remodelling and angiogenesis during embryo implantation (Dobrzyn et al. 2024). Finally, another study in pigs described the upregulation of another adipokine, the RBP4, in the endometrium between days 11 and 18 of pregnancy, highlighting its role in embryo implantation (Wang et al. 2023). In conclusion, maternal obesity may induce significant changes in the activity of adipokines beyond leptin, including adiponectin, chemerin, apelin and RBP4, which collectively affect endometrial function, decidualisation and the establishment of pregnancy.
Impaired decidualisation in obese mothers: clinical outcomes
Deficient decidualisation poses a significant risk for adverse pregnancy outcomes, including pre-eclampsia, intrauterine FGR and an increased incidence of neonatal mortality (Rhee et al. 2016, Ticconi et al. 2021). For instance, alterations in cell cycle regulation, such as the dysregulation of decidual senescence, can lead to complications in embryo implantation and abnormal placental development. Decidual senescence is characterised by the arrest of the cell cycle, in which cells cease to proliferate and differentiate while remaining metabolically active (Childs et al. 2017). Whereas excessive cellular senescence of the decidua was observed in recurrent miscarriage, insufficient senescence was linked to failed embryo implantation (Deryabin & Borodkina 2022). Furthermore, research on mice revealed that the uterine deletion of Trp53 resulted in preterm birth with foetal death, accompanied by impaired decidualisation and increased expression of cell senescence genes such as pAkt, p21 and Cox2 in the decidua (Hirota et al. 2010). Thus, the coordinated regulation of decidual senescence is essential for successful pregnancy outcomes.
Research indicates that the decidua plays a major role in the extensive remodelling of the uterine spiral arteries (Zhang & Wei 2021). The deficient reorganisation of the spiral arteries is closely associated with the occurrence of pre-eclampsia. Moreover, insufficient trophoblast invasion into the decidua has been identified as a potential precursor of pre-eclampsia (Staff et al. 2022). Garrido-Gomez and coworkers uncovered a distinct transcriptional fingerprint in women with severe pre-eclampsia, indicating that defects in endometrial decidualisation could lead to impaired cytotrophoblast invasion (Garrido-Gomez et al. 2021). Another repercussion of defective decidualisation is recurrent pregnancy loss, which is defined by the occurrence of three or more consecutive miscarriages (El Hachem et al. 2017). While the exact cause is unclear, recent research suggests that women with recurrent pregnancy loss may have impaired decidualisation due to altered hormonal response and the altered expression of decidualisation genes such as prolactin (PRL), iodothyronine deiodinase 2 (DIO2) and scavenger receptor class A member 5 (SCARA5) (Lucas et al. 2020). The effective decidualisation of endometrial stromal cells is essential for healthy pregnancy outcomes. Maternal obesity further contributes to impaired decidualisation, as obesity-associated hormonal imbalance and adipokine signalling may disrupt endometrial function. Furthermore, elevated leptin levels in obese individuals can lead to dysregulated angiogenesis and immune response, contributing to conditions such as pre-eclampsia and recurrent pregnancy loss. These insights underpin the importance of altered metabolic performance in obese mothers for decidualisation and successful embryo implantation and pregnancy.
Conclusion
In conclusion, an optimal regulation of decidualisation is critical for successful pregnancy establishment (Rhee et al. 2016). Understanding the molecular and cellular mechanisms involved in decidualisation offers potential avenues for therapeutic interventions, to mitigate adverse outcomes and improve reproductive health in obese mothers. Leptin appears as a pivotal contributor to the pathogenesis of impaired decidualisation in obese mothers, contributing to an exacerbated inflammatory response, altered ECM deposition or compromised angiogenesis and deficient reorganisation of the endometrial vascular bed (Fig. 4) (Walewska et al. 2024). Consequently, implantation and placentation will be compromised. Additionally, the extent to which altered endometrial leptin signalling affects trophoblast proliferation and differentiation demands further investigation (Smolinska et al. 2009, Galio et al. 2023). Targeted approaches to leptin regulation could help mitigate the risks of pregnancy complications in obese mothers.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by a grant (No. 2019/34/E/NZ4/00349) from the Polish National Science Centre and the Comparative Biomedical Sciences Departmental fund from the Royal Veterinary College attributed to AG and a grant (No. 2019/35/N/NZ4/03496) from the Polish National Science Centre attributed to EW.
Author contribution statement
EW conceptualised the study, prepared the original draft and edited the text; ZH performed acquisition, analysis and interpretation of the data; VP-G wrote and edited the text; and AG conceptualised and supervised the study and wrote and edited the text. All authors have reviewed and approved the manuscript for publication.
Acknowledgements
We would like to thank Dr Gavin Kelsey, Epigenetics Programme, Babraham Institute, UK, for the editorial support provided.
References
Ahn JH, Choi YS & Choi JH 2015 Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway. Mol Hum Reprod 21 792–802. (https://doi.org/10.1093/MOLEHR/GAV039)
Anim-Nyame N, Sooranna SR, Steer PJ, et al. 2000 Longitudinal analysis of maternal plasma leptin concentrations during normal pregnancy and pre-eclampsia. Hum Reprod 15 2033–2036. (https://doi.org/10.1093/HUMREP/15.9.2033)
Ardid-ruiz A, Ibars M & Su M 2016 Modulation of leptin resistance by food compounds. Mol Nutr Food Res 60 1789–1803. (https://doi.org/10.1002/mnfr.201500964)
Arias-Álvarez M, García-García RM, Torres-Rovira L, et al. 2010 Influence of leptin on in vitro maturation and steroidogenic secretion of cumulus-oocyte complexes through JAK2/STAT3 and MEK 1/2 pathways in the rabbit model. Reproduction 139 523–532. (https://doi.org/10.1530/REP-09-0309)
Baltayeva J, Konwar C, Castellana B, et al. 2019 Obesogenic diet exposure alters uterine natural killer cell biology and impairs vasculature remodeling in mice. Biol Reprod 102 63–75. (https://doi.org/10.1093/biolre/ioz163)
Bazzano MV, Sarrible GB, Berón de Astrada M, et al. 2021 Obesity modifies the implantation window and disrupts intrauterine embryo positioning in rats. Reproduction 162 61–72. (https://doi.org/10.1530/REP-21-0015)
Beck C, Allshouse AA, Blue NR, et al. 2021 1072 early pregnancy BMI and angiogenesis-related biomarkers (sFlt-1/PlGF): a pathway for adverse pregnancy outcomes? Am J Obstet Gynecol 224 S662–S663. (https://doi.org/10.1016/j.ajog.2020.12.1097)
Beck C, Allshouse A, Silver RM, et al. 2022 High early pregnancy body mass index is associated with alterations in first- and second-trimester angiogenic biomarkers. Am J Obstet Gynecol MFM 4 100614. (https://doi.org/10.1016/j.ajogmf.2022.100614)
Bijovsky AT, Zorn TMT & Abrahamsohn PA 1992 Remodeling of the mouse endometrial stroma during the preimplantation period. Acta Anatomica 144 231–234. (https://doi.org/10.1159/000147311)
Bouillon-Minois JB, Trousselard M, Thivel D, et al. 2021 Leptin as a biomarker of stress: a systematic review and meta-analysis. Nutrients 13 3350. (https://doi.org/10.3390/NU13103350)
Cao R, Brakenhielm E, Wahlestedt C, et al. 2001 Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A 98 6390–6395. (https://doi.org/10.1073/pnas.101564798)
Carino C, Olawaiye AB, Cherfils S, et al. 2008 Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells. Int J Cancer 123 2782–2790. (https://doi.org/10.1002/ijc.23887)
Castellucci M, De Matteis R, Meisser A, et al. 2000 Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Mol Hum Reprod 6 951–958. (https://doi.org/10.1093/MOLEHR/6.10.951)
Castillo-Castrejon M & Powell TL 2017 Placental nutrient transport in gestational diabetic pregnancies. Front Endocrinol 8 306. (https://doi.org/10.3389/fendo.2017.00306)
Catalano S, Giordano C, Rizza P, et al. 2009 Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol 218 490–500. (https://doi.org/10.1002/jcp.21622)
Cha J, Sun X & Dey SK 2012 Mechanisms of implantation: strategies for successful pregnancy. Nat Med 18 1754–1767. (https://doi.org/10.1038/nm.3012)
Chen Z, E Y, Xiong J, et al. 2023 Dysregulated glycolysis underpins high-fat-associated endometrial decidualization impairment during early pregnancy in mice. Biochim Biophys Acta Mol Basis Dis 1869 166659. (https://doi.org/10.1016/J.BBADIS.2023.166659)
Childs BG, Gluscevic M, Baker DJ, et al. 2017 Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 16 718–735. (https://doi.org/10.1038/nrd.2017.116)
Clarke GS, Vincent AD, Ladyman SR, et al. 2024 Circadian patterns of behaviour change during pregnancy in mice. J Physiol 602 6531–6552. (https://doi.org/10.1113/JP285553)
Conneely OM & Lydon JP 2000 Progesterone receptors in reproduction: functional impact of the A and B isoforms. Steroids 65 571–577. (https://doi.org/10.1016/S0039-128X(00)00115-X)
Croy BA, He H, Esadeg S, et al. 2003 Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling. Reproduction 126 149–160. (https://doi.org/10.1530/rep.0.1260149)
Curtis SW, Clark J, Myers P, et al. 1999 Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor α knockout mouse uterus. Proc Natl Acad Sci U S A 96 3646–3651. (https://doi.org/10.1073/PNAS.96.7.3646)
Das SK 2009 Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction 137 889–899. (https://doi.org/10.1530/REP-08-0539)
Dawid M, Pich K, Mlyczyńska E, et al. 2024 Adipokines in pregnancy. Adv Clin Chem 121 172–269. (https://doi.org/10.1016/BS.ACC.2024.04.006)
de Knegt VE, Hedley PL, Kanters JK, et al. 2021 The role of leptin in fetal growth during pre-eclampsia. Int J Mol Sci 22 4569. (https://doi.org/10.3390/ijms22094569)
Dearden L & Ozanne SE 2023 Early life impacts of maternal obesity: a window of opportunity to improve the health of two generations. Philos Trans R Soc Lond B Biol Sci 378 20220222. (https://doi.org/10.1098/RSTB.2022.0222)
Deryabin PI & Borodkina AV 2022 Stromal cell senescence contributes to impaired endometrial decidualization and defective interaction with trophoblast cells. Hum Reprod 37 1505–1524. (https://doi.org/10.1093/HUMREP/DEAC112)
Do Carmo, JM, Da Silva, AA, Wang, Z, et al. 2016 Regulation of blood pressure, appetite, and glucose by leptin after inactivation of insulin receptor substrate 2 signaling in the entire brain or in proopiomelanocortin neurons. Hypertension 67 378–386. (https://doi.org/10.1161/HYPERTENSIONAHA.115.06153)
Dobrzyn K, Kiezun M, Kopij G, et al. 2024 Apelin-13 modulates the endometrial transcriptome of the domestic pig during implantation. BMC Genomics 25 501–516. (https://doi.org/10.1186/S12864-024-10417-9/FIGURES/6)
El Hachem H, Crepaux V, May-Panloup P, et al. 2017 Recurrent pregnancy loss: current perspectives. Int J Women’s Health 9 331–345. (https://doi.org/10.2147/IJWH.S100817)
Elmore SA, Cochran RZ, Bolon B, et al. 2022 Histology atlas of the developing mouse placenta. Toxicologic Pathol 50 60–117. (https://doi.org/10.1177/01926233211042270)
Fang Y, Cao D, Chan RWS, et al. 2023 P-796 Single-cell transcriptomics unveils a role for leptin receptor in human endometrial mesenchymal stromal/stem cells. Hum Reprod 38 (Supp. 1). (https://doi.org/10.1093/HUMREP/DEAD093.1102)
Faulkner JL, Wright D, Antonova G, et al. 2022 Midgestation leptin infusion induces characteristics of clinical preeclampsia in mice, which is ablated by endothelial mineralocorticoid receptor deletion. Hypertension 79 1536–1547. (https://doi.org/10.1161/HYPERTENSIONAHA.121.18832)
Favaro R, Abrahamsohn PA & Zorn MT 2014 Decidualization and endometrial extracellular matrix remodeling. Guide Invest Mouse Pregnancy 245 125–142. (https://doi.org/10.1016/B978-0-12-394445-0.00011-4)
Francisco V, Pino J, Campos-Cabaleiro V, et al. 2018 Obesity, fat mass and immune system: role for leptin. Front Physiol 9 640. (https://doi.org/10.3389/fphys.2018.00640)
Frehner BL, Reichler IM, Kowalewski MP, et al. 2021 Implications of the RhoA/Rho associated kinase pathway and leptin in primary uterine inertia in the dog. J Reprod Dev 67 207–215. (https://doi.org/10.1262/JRD.2020-141)
Fukuda J, Nasu K, Sun B, et al. 2003 Effects of leptin on the production of cytokines by cultured human endometrial stromal and epithelial cells. Fertil Steril 80 783–787. (https://doi.org/10.1016/S0015-0282(03)
Galio L, Bernet L, Rodriguez Y, et al. 2023 The effect of obesity on uterine receptivity is mediated by endometrial extracellular vesicles that control human endometrial stromal cell decidualization and trophoblast invasion. J Extracellular Biol 2 e103. (https://doi.org/10.1002/JEX2.103)
Gao X, Li Y, Ma Z, et al. 2021 Obesity induces morphological and functional changes in female reproductive system through increases in NF-κB and MAPK signaling in mice. Reprod Biol Endocrinol 19 148–215. (https://doi.org/10.1186/S12958-021-00833-X/FIGURES/9)
Garonna E, Botham KM, Birdsey GM, et al. 2011 Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells. PLoS One 6 e18823. (https://doi.org/10.1371/JOURNAL.PONE.0018823)
Garrido-Gomez T, Castillo-Marco N, Clemente-Ciscar M, et al. 2021 Disrupted pgr-b and esr1 signaling underlies defective decidualization linked to severe preeclampsia. ELife 10 e70753. (https://doi.org/10.7554/ELIFE.70753)
Gavrilova O, Barr V, Marcus-Samuels B, et al. 1997 Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor. J Biol Chem 272 30546–30551. (https://doi.org/10.1074/JBC.272.48.30546)
Gellersen B, Brosens IA & Brosens JJ 2007 Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med 25 445–453. (https://doi.org/10.1055/S-2007-991042)
González RR, Caballero-Campo P, Jasper M, et al. 2000 Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J Clin Endocrinol Metab 85 4883–4888. (https://doi.org/10.1210/JCEM.85.12.7060)
Gorska E, Popko K, Stelmaszczyk-Emmel A, et al. 2010 Leptin receptors. Eur J Med Res 15 (Supplement 2) 50. (https://doi.org/10.1186/2047-783X-15-S2-50)
Gudelska M, Dobrzyn K, Kiezun M, et al. 2020 The expression of chemerin and its receptors (CMKLR1, GPR1, CCRL2) in the porcine uterus during the oestrous cycle and early pregnancy and in trophoblasts and conceptuses. Animal 14 2116–2128. (https://doi.org/10.1017/S175173112000097X)
Gustafson P, Ladyman SR & Brown RSE 2019 Suppression of leptin transport into the brain contributes to leptin resistance during pregnancy in the mouse. Endocrinology 160 880–890. (https://doi.org/10.1210/EN.2018-01065)
Hadden DR & McLaughlin C 2009 Normal and abnormal maternal metabolism during pregnancy. Semin Fetal Neonatal Med 14 66–71. (https://doi.org/10.1016/j.siny.2008.09.004)
Han DC, Isono M, Chen S, et al. 2001 Leptin stimulates type I collagen production in db/db mesangial cells: glucose uptake and TGF-β type II receptor expression. Kidney Int 59 1315–1323. (https://doi.org/10.1046/j.1523-1755.2001.0590041315.x)
Helker CS, Eberlein J, Wilhelm K, et al. 2020 Apelin signaling drives vascular endothelial cells toward a pro-angiogenic state. eLife 9 e55589. (https://doi.org/10.7554/eLife.55589)
Henson MC & Castracane VD 2000 Leptin in pregnancy. Biol Reprod 63 1219–1228. (https://doi.org/10.1095/BIOLREPROD63.5.1219)
Hirota Y, Daikoku T, Tranguch S, et al. 2010 Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice. J Clin Invest 120 803–815. (https://doi.org/10.1172/JCI40051)
Hu C, Yang Y, Li J, et al. 2019 Maternal diet-induced obesity compromises oxidative stress status and angiogenesis in the porcine placenta by upregulating Nox2 expression. Oxidative Med Cell Longevity 2019 2481592. (https://doi.org/10.1155/2019/2481592)
Iikuni N, Kwan Lam Q, Lu L, et al. 2008 Leptin and inflammation. Curr Immunol Rev 4 70–79. (https://doi.org/10.2174/157339508784325046)
Iwakura H, Dote K, Bando M, et al. 2016 Establishment of leptin-responsive cell lines from adult mouse hypothalamus. PLoS One 11 e0148639. (https://doi.org/10.1371/journal.pone.0148639)
Kabbani N, Blüher M, Stepan H, et al. 2023 Adipokines in pregnancy: a systematic review of clinical data. Biomedicines 11 1419. (https://doi.org/10.3390/BIOMEDICINES11051419/S1)
Kasacka I, Piotrowska Ż, Niezgoda M, et al. 2019 Differences in leptin biosynthesis in the stomach and in serum leptin level between men and women. J Gastroenterol Hepatol 34 1922–1928. (https://doi.org/10.1111/JGH.14688)
Kent L, McGirr M & Eastwood KA 2024 Global trends in prevalence of maternal overweight and obesity: a systematic review and meta-analysis of routinely collected data retrospective cohorts. Int J Popul Data Sci 9 06. (https://doi.org/10.23889/ijpds.v9i2.2401)
Khant Aung Z, Grattan DR & Ladyman SR 2020 Pregnancy-induced adaptation of central sensitivity to leptin and insulin. Mol Cell Endocrinol 516 110933. (https://doi.org/10.1016/J.MCE.2020.110933)
Kim ST, Marquard K, Stephens S, et al. 2011 Adiponectin and adiponectin receptors in the mouse preimplantation embryo and uterus. Hum Reprod 26 82–95. (https://doi.org/10.1093/HUMREP/DEQ292)
Kirn-Safran CB, D’Souza SS & Carson DD 2008 Heparan sulfate proteoglycans and their binding proteins in embryo implantation and placentation. Semin Cell Dev Biol 19 187–193. (https://doi.org/10.1016/j.semcdb.2007.07.013)
Koshiba, H, Kitawaki, J, Ishihara, H, et al. 2001 Progesterone inhibition of functional leptin receptor mRNA expression in human endometrium. Mol Hum Reprod 7 567–572. (https://doi.org/10.1093/molehr/7.6.567)
La Cava A 2017 Leptin in inflammation and autoimmunity. Cytokine 98 51–58. (https://doi.org/10.1016/j.cyto.2016.10.011)
Landt M, Lawson GM, Helgeson JM, et al. 1997 Prolonged exercise decreases serum leptin concentrations. Metab Clin Exp 46 1109–1112. (https://doi.org/10.1016/S0026-0495(97)90200-6)
Large MJ & DeMayo FJ 2012 The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling. Mol Cell Endocrinol 358 155–165. (https://doi.org/10.1016/J.MCE.2011.07.027)
Lee CH, Kim TH, Lee JH, et al. 2013 Extracellular signal-regulated kinase 1/2 signaling pathway is required for endometrial decidualization in mice and human. PLoS One 8 e75282. (https://doi.org/10.1371/journal.pone.0075282)
Lewandowska M 2021 Maternal obesity and risk of low birth weight, fetal growth restriction, and macrosomia: multiple analyses. Nutrients 13 1213. (https://doi.org/10.3390/nu13041213)
Li, Y, Chen, X, Gong, X, et al. 2022 Effect of gender on serum leptin in type 2 diabetes mellitus: a system review and meta-analysis. Comput Math Methods Med 2022 4875799. (https://doi.org/10.1155/2022/4875799)
Lijnen HR 2008 Angiogenesis and obesity. Cardiovasc Res 78 286–293. (https://doi.org/10.1093/CVR/CVM007)
Lima PDA, Zhang J, Dunk C, et al. 2014 Leukocyte driven-decidual angiogenesis in early pregnancy. Cell Mol Immunol 11 522–537. (https://doi.org/10.1038/cmi.2014.63)
Linnemann K, Malek A, Sager R, et al. 2000 Leptin production and release in the dually in VitroPerfused human placenta. J Clin Endocrinol Metab 85 4298–4301. (https://doi.org/10.1210/JCEM.85.11.6933)
Liu Y, Lv L, Xiao W, et al. 2011 Leptin activates STAT3 and ERK1/2 pathways and induces endometrial cancer cell proliferation. J Huazhong Univ Sci Technol Med Sci 31 365–370. (https://doi.org/10.1007/S11596-011-0382-7)
Liu R, Dai M, Gong G, et al. 2022 The role of extracellular matrix on unfavorable maternal–fetal interface: focusing on the function of collagen in human fertility. J Leather Sci Eng 4 13. (https://doi.org/10.1186/s42825-022-00087-2)
Löffler S, Aust G, Köhler U, et al. 2001 Evidence of leptin expression in normal and polycystic human ovaries. Molecular Human Reproduction 7 1143–1149. (https://doi.org/10.1093/molehr/7.12.1143)
Loh K, Fukushima A, Zhang X, et al. 2011 Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab 14 684–699. (https://doi.org/10.1016/J.CMET.2011.09.011)
Lu Z, Hardt J & Kim JJ 2008 Global analysis of genes regulated by HOXA10 in decidualization reveals a role in cell proliferation. Mol Hum Reprod 14 357–366. (https://doi.org/10.1093/MOLEHR/GAN023)
Lu P, Takai K, Weaver VM, et al. 2011 Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor Perspect Biol 3 a005058. (https://doi.org/10.1101/cshperspect.a005058)
Lucas ES, Vrljicak P, Muter J, et al. 2020 Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window. Commun Biol 3 37. (https://doi.org/10.1038/S42003-020-0763-1)
Massri N, Loia R, Sones JL, et al. 2023 Vascular changes in the cycling and early pregnant uterus. JCI Insight 8 e163422. (https://doi.org/10.1172/jci.insight.163422)
Masuzaki H, Ogawa Y, Sagawa N, et al. 1997 Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3 1029–1033. (https://doi.org/10.1038/NM0997-1029)
Maymó JL, Pérez Pérez A, Dueñas JL, et al. 2010 Regulation of placental leptin expression by cyclic adenosine 5’-monophosphate involves cross talk between protein kinase A and mitogen-activated protein kinase signaling pathways. Endocrinology 151 3738–3751. (https://doi.org/10.1210/EN.2010-0064)
Mlyczyńska E, Kurowska P, Drwal E, et al. 2020 Apelin and apelin receptor in human placenta: Expression, signalling pathway and regulation of trophoblast JEG‑3 and BeWo cells proliferation and cell cycle. Int J Mol Med 45 691–702. (https://doi.org/10.3892/ijmm.2020.4452)
Mori M, Bogdan A, Balassa T, et al. 2016 The decidua—the maternal bed embracing the embryo—maintains the pregnancy. Semin Immunopathol 38 635–649. (https://doi.org/10.1007/S00281-016-0574-0)
Murata H, Tanaka S & Okada H 2022 The regulators of human endometrial stromal cell decidualization. Biomolecules 12 1275. (https://doi.org/10.3390/biom12091275)
Myers M 2004a Leptin receptor signaling and the regulation of mammalian physiology. Endocr Soc 59 287–304. (https://doi.org/10.1210/rp.59.1.287)
Myers MG 2004b Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 59 287–304. (https://doi.org/10.1210/RP.59.1.287)
Myers MG, Cowley MA & Münzberg H 2008 Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70 537–556. (https://doi.org/10.1146/ANNUREV.PHYSIOL.70.113006.100707)
Ng SW, Norwitz GA, Pavlicev M, et al. 2020a Endometrial decidualization: the primary driver of pregnancy health. Int J Mol Sci 21 4092–4120. (https://doi.org/10.3390/ijms21114092)
Ng SW, Norwitz GA, Pavlicev M, et al. 2020b Endometrial decidualization: the primary driver of pregnancy health. Int J Mol Sci 21 4092–4120. (https://doi.org/10.3390/ijms21114092)
Niu L, Wang X, Li J, et al. 2007 Leptin stimulates α1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway. Liver Int 27 1265–1272. (https://doi.org/10.1111/j.1478-3231.2007.01582.x)
Oestreich AK & Moley KH 2017 Developmental and transmittable origins of obesity-associated health disorders. Trends Genet 33 399–407. (https://doi.org/10.1016/j.tig.2017.03.008)
Oh HK, Choi YS, Yang YI, et al. 2013 Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. Mol Hum Reprod 19 160–168. (https://doi.org/10.1093/MOLEHR/GAS055)
Orzechowska K, Dobrzyń K, Kieżun M, et al. 2022 Chemerin effect on the endometrial proteome of the domestic pig during implantation obtained by LC-MS/MS analysis. Cells 11 1161. (https://doi.org/10.3390/cells11071161)
Ostlund RE, Yang JW, Klein S, et al. 1996 Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates. J Clin Endocrinol Metab 81 3909–3913. (https://doi.org/10.1210/JCEM.81.11.8923837)
Peltokorpi A, Irina L, Liisa V, et al. 2022 Preconceptual leptin levels in gestational diabetes and hypertensive pregnancy. Hypertens Pregnancy 41 70–77. (https://doi.org/10.1080/10641955.2022.2033763)
Peng H, Wei M, Huang L, et al. 2022 Maternal obesity inhibits placental angiogenesis by down-regulating the SIRT1/PGC-1α pathway. Ann Translational Med 10 446. (https://doi.org/10.21037/ATM-22-1221)
Pérez-Pérez A, Toro A, Vilariño-García T, et al. 2018 Leptin action in normal and pathological pregnancies. J Cell Mol Med 22 716–727. (https://doi.org/10.1111/jcmm.13369)
Picardi PK, Caricilli AM, Lelis L, et al. 2010 Modulation of hypothalamic PTP1B in the TNF-a-induced insulin and leptin resistance. FEBS Lett 584 3179–3184. (https://doi.org/10.1016/j.febslet.2010.05.064)
Plaisier M 2011 Decidualization and angiogenesis. Best Pract Res Clin Obstet Gynaecol 25 259–271. (https://doi.org/10.1016/J.BPOBGYN.2010.10.011)
Plaisier M, Dennert I, Rost E, et al. 2008 Decidual vascularization and the expression of angiogenic growth factors and proteases in first trimester spontaneous abortions. Hum Reprod 24 185–197. (https://doi.org/10.1093/HUMREP/DEN296)
Potdar N & Iyasere C 2023 Early pregnancy complications including recurrent pregnancy loss and obesity. Best Pract Res Clin Obstet Gynaecol 90 102372. (https://doi.org/10.1016/J.BPOBGYN.2023.102372)
Ptak A, Kolaczkowska E & Gregoraszczuk EL 2013 Leptin stimulation of cell cycle and inhibition of apoptosis gene and protein expression in OVCAR-3 ovarian cancer cells. Endocrine 43 394–403. (https://doi.org/10.1007/s12020-012-9788-7)
Ramathal CY, Bagchi IC, Taylor RN, et al. 2010 Endometrial decidualization: of mice and men. Semin Reprod Med 28 017–026. (https://doi.org/10.1055/s-0029-1242989)
Reitman ML, Bi S, Marcus-Samuels B, et al. 2001 Leptin and its role in pregnancy and fetal development—an overview. Biochem Soc Trans 29 68–72. (https://doi.org/10.1042/BST0290068)
Reschke L, Afrin S, El Sabah M, et al. 2022 Leptin induces leiomyoma cell proliferation and extracellular matrix deposition via JAK2/STAT3 and MAPK/ERK pathways. F S Sci 3 383–391. (https://doi.org/10.1016/j.xfss.2022.05.001)
Rhee JS, Saben JL, Mayer AL, et al. 2016 Diet-induced obesity impairs endometrial stromal cell decidualization: a potential role for impaired autophagy. Hum Reprod 31 1315–1326. (https://doi.org/10.1093/HUMREP/DEW048)
Robles TG, Fernández RAG, García-Palencia P, et al. 2017 Hoxa-10 and cyclin D3 overexpression in the decidual reaction in a superovulation protocol in young adult C57BL/6J mice. Vet Pathol 54 328–335. (https://doi.org/10.1177/0300985816660748)
Rock FL, Altmann SW, Van Heek M, et al. 1996 The liptin haemopoietic cytokine fold is stabilized by an intrachain disulfide bond. Horm Metab Res 28 649–652. (https://doi.org/10.1055/S-2007-979871)
Różycka M, Kurowska P, Grzesiak M, et al. 2018 Apelin and apelin receptor at different stages of corpus luteum development and effect of apelin on progesterone secretion and 3β-hydroxysteroid dehydrogenase (3β-HSD) in pigs. Anim Reprod Sci 192 251–260. (https://doi.org/10.1016/J.ANIREPROSCI.2018.03.021)
Rui L 2014 SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 5 511. (https://doi.org/10.4239/WJD.V5.I4.511)
Saben JL, Asghar Z, Rhee JS, et al. 2016 Excess maternal fructose consumption increases fetal loss and impairs endometrial decidualization in mice. Endocrinology 157 956–968. (https://doi.org/10.1210/en.2015-1618)
Saladin R, De Vos P, Guerre-Millot M, et al. 1995 Transient increase in obese gene expression after food intake or insulin administration. Nature 377 527–528. (https://doi.org/10.1038/377527a0)
Salem AM 2021 Variation of leptin during menstrual cycle and its relation to the hypothalamic-pituitary-gonadal (HPG) Axis: a systematic review. Int J Women’s Health 13 445–458. (https://doi.org/10.2147/IJWH.S309299)
Salmasi S, Sharifi M & Rashidi B 2021 Ovarian stimulation and exogenous progesterone affect the endometrial miR-16-5p, VEGF protein expression, and angiogenesis. Microvasc Res 133 104074. (https://doi.org/10.1016/j.mvr.2020.104074)
Sánchez-Jiménez F, Pérez-Pérez A, de la Cruz-Merino L, et al. 2019 Obesity and breast cancer: role of leptin. Front Oncol 9 596. (https://doi.org/10.3389/fonc.2019.00596)
Sarankhuu BE, Jeon HJ, Jeong DU, et al. 2024 Adiponectin receptor 1 regulates endometrial receptivity via the adenosine monophosphate-activated protein kinase/E-cadherin pathway. Mol Med Rep 30 184. (https://doi.org/10.3892/MMR.2024.13308)
Sessions-Bresnahan DR, Heuberger AL & Carnevale EM 2018 Obesity in mares promotes uterine inflammation and alters embryo lipid fingerprints and homeostasis. Biol Reprod 99 761–772. (https://doi.org/10.1093/BIOLRE/IOY107)
Shao J, Li MQ, Meng YH, et al. 2013 Estrogen promotes the growth of decidual stromal cells in human early pregnancy. Mol Hum Reprod 19 655–664. (https://doi.org/10.1093/MOLEHR/GAT034)
Shen W, Tian C, Chen H, et al. 2013 Oxidative stress mediates chemerin-induced autophagy in endothelial cells. Free Radic Biol Med 55 73–82. (https://doi.org/10.1016/J.FREERADBIOMED.2012.11.011)
Shi JW, Lai ZZ, Yang HL, et al. 2020 Collagen at the maternal-fetal interface in human pregnancy. Int J Biol Sci 16 2220–2234. (https://doi.org/10.7150/ijbs.45586)
Shu Z, Row S & Deng WM 2018 Endoreplication: the good, the bad, and the ugly. Trends Cell Biol 28 465–474. (https://doi.org/10.1016/j.tcb.2018.02.006)
Silvestris E, de Pergola G, Rosania R, et al. 2018 Obesity as disruptor of the female fertility. Reprod Biol Endocrinol 16 22. (https://doi.org/10.1186/s12958-018-0336-z)
Smolinska N, Kaminski T, Siawrys G, et al. 2009 Long form of leptin receptor gene and protein expression in the porcine trophoblast and uterine tissues during early pregnancy and the oestrous cycle. Anim Reprod Sci 113 125–136. (https://doi.org/10.1016/j.anireprosci.2008.06.001)
Spiess K, Teodoro WR & Zorn TMT 2007 Distribution of collagen types I, III and V in pregnant mouse endometrium. Connect Tissue Res 48 99–108. (https://doi.org/10.1080/03008200601166194)
Staff AC, Fjeldstad HE, Fosheim IK, et al. 2022 Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia. Am J Obstet Gynecol 226 S895–S906. (https://doi.org/10.1016/j.ajog.2020.09.026)
Stefaniak M, Dmoch-Gajzlerska E, Mazurkiewicz B, et al. 2019 Maternal serum and cord blood leptin concentrations at delivery. PLoS One 14 e0224863. (https://doi.org/10.1371/JOURNAL.PONE.0224863)
St-Germain LE, Castellana B, Baltayeva J, et al. 2020 Maternal obesity and the uterine immune cell landscape: the shaping role of inflammation. Int J Mol Sci 21 3776. (https://doi.org/10.3390/ijms21113776)
Styer AK, Gonzalez RR, Ramos P, et al. 2004 The role of leptin in endometrial proliferation. Fertil Steril 82 S309. (https://doi.org/10.1016/j.fertnstert.2004.07.834)
Tahergorabi Z & Khazaei M 2015 Leptin and its cardiovascular effects: focus on angiogenesis. Adv Biomed Res 4 79. (https://doi.org/10.4103/2277-9175.156526)
Tan J, Paria BC, Dey SK, et al. 1999 Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse. Endocrinology 140 5310–5321. (https://doi.org/10.1210/ENDO.140.11.7148)
Tan J, Raja S, Davis MK, et al. 2002 Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation. Mech Dev 111 99–113. (https://doi.org/10.1016/S0925-4773(01)00614-1)
Ticconi C, Di Simone N, Campagnolo L, et al. 2021 Clinical consequences of defective decidualization. Tissue and Cell 72 101586. (https://doi.org/10.1016/J.TICE.2021.101586)
Tomimatsu T, Yamaguchi M, Murakami T, et al. 1997 Increase of mouse leptin production by adipose tissue after midpregnancy: gestational profile of serum leptin concentration. Biochem Biophysical Res Commun 240 213–215. (https://doi.org/10.1006/BBRC.1997.7638)
Walewska E, Makowczenko KG, Witek K, et al. 2024 Fetal growth restriction and placental defects in obese mice are associated with impaired decidualization: the role of increased leptin signalling modulators SOCS3 and PTPN2. Cell Mol Life Sci 81 329. (https://doi.org/10.1007/s00018-024-05336-7)
Wanaditya GK, Putra IWA, Aryana MBD, et al. 2023 Obesity in pregnant women and its impact on maternal and neonatal morbidity. Eur J Med Health Sci 5 17–21. (https://doi.org/10.24018/EJMED.2023.5.3.1625)
Wang H, Cheng H, Shao Q, et al. 2014 Leptin-promoted human extravillous trophoblast invasion is MMP14 dependent and requires the cross talk between Notch1 and PI3K/Akt signaling. Biol Reprod 90 78. (https://doi.org/10.1095/BIOLREPROD.113.114876)
Wang H, Fu J & Wang A 2020 Leptin upregulates the expression of β3-integrin, MMP9, HB-EGF, and IL-1β in primary porcine endometrium epithelial cells in vitro. Int J Environ Res Public Health 17 6508. (https://doi.org/10.3390/IJERPH17186508)
Wang Y, Xue S, Liu Q, et al. 2023 Proteomic profiles and the function of RBP4 in endometrium during embryo implantation phases in pigs. BMC Genomics 24 200. (https://doi.org/10.1186/S12864-023-09278-5)
Weihua Z, Saji S, Mäkinen S, et al. 2000 Estrogen receptor (ER) β, a modulator of ERα in the uterus. Proc Natl Acad Sci U S A 97 5936–5941. (https://doi.org/10.1073/PNAS.97.11.5936)
Wołodko K, Walewska E, Adamowski M, et al. 2020 Leptin resistance in the ovary of obese mice is associated with profound changes in the transcriptome of cumulus cells. Cell Physiol Biochem 54 417–437. (https://doi.org/10.33594/000000228)
Wołodko K, Castillo‐fernandez J, Kelsey G, et al. 2021 Revisiting the impact of local leptin signaling in folliculogenesis and oocyte maturation in obese mothers. Int J Mol Sci 22 4270. (https://doi.org/10.3390/IJMS22084270/S1)
Woods L, Perez-garcia V & Hemberger M 2018 Regulation of placental development and its impact on fetal growth—new insights from mouse models. Front Endocrinol 9 570. (https://doi.org/10.3389/fendo.2018.00570)
World Health Organization 2016 Media centre obesity and overweight. (https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight)
World Obesity Federation 2024 One billion people globally estimated to be living with obesity by 2030. (https://www.worldobesity.org/news/one-billion-people-globally-estimated-to-be-living-with-obesity-by-2030). Accessed on 8 March 2024.
Xu M, Cao FL, Li N, et al. 2018 Leptin induces epithelial-to-mesenchymal transition via activation of the ERK signaling pathway in lung cancer cells. Oncol Lett 16 4782–4788. (https://doi.org/10.3892/OL.2018.9230)
Yin Y, Wang A, Feng L, et al. 2018 Heparan sulfate proteoglycan sulfation regulates uterine differentiation and signaling during embryo implantation. Endocrinology 159 2459–2472. (https://doi.org/10.1210/en.2018-00105)
Yu F, Fu R, Liu L, et al. 2019 Leptin-induced angiogenesis of EA.HY926 endothelial cells via the Akt and Wnt signaling pathways in vitro and in vivo. Front Pharmacol 10 1275. (https://doi.org/10.3389/fphar.2019.01275)
Zeng S, Liu Y, Fan P, et al. 2023 Role of leptin in the pathophysiology of preeclampsia. Placenta 142 128–134. (https://doi.org/10.1016/J.PLACENTA.2023.09.005)
Zhang Y & Scarpace PJ 2006 The role of leptin in leptin resistance and obesity. Physiol Behav 88 249–256. (https://doi.org/10.1016/j.physbeh.2006.05.038)
Zhang X & Wei H 2021 Role of decidual natural killer cells in human pregnancy and related pregnancy complications. Front Immunol 12 728291. (https://doi.org/10.3389/FIMMU.2021.728291)
Zhang Q, Xiao Z, Lee CL, et al. 2022 The regulatory roles of chemerin-chemokine-like receptor 1 axis in placental development and vascular remodeling during early pregnancy. Front Cell Dev Biol 10 883636. (https://doi.org/10.3389/FCELL.2022.883636)
Zhang X, Ha S, Lau HCH, et al. 2023 Excess body weight: novel insights into its roles in obesity comorbidities. Semin Cancer Biol 92 16–27. (https://doi.org/10.1016/J.SEMCANCER.2023.03.008)
Zhao F, Liu H, Wang N, et al. 2020 Exploring the role of Luman/CREB3 in regulating decidualization of mice endometrial stromal cells by comparative transcriptomics. BMC Genomics 21 103. (https://doi.org/10.1186/s12864-020-6515-2)
Zhao YQ, Ren YF, Li BB, et al. 2024 The mysterious association between adiponectin and endometriosis. Front Pharmacol 15 1396616. (https://doi.org/10.3389/FPHAR.2024.1396616)
Zheng L, Yang L, Guo Z, et al. 2024 Obesity and its impact on female reproductive health: unraveling the connections. Front Endocrinol 14 1326546. (https://doi.org/10.3389/FENDO.2023.1326546)
Zhu H, Hou CC, Luo LF, et al. 2014 Endometrial stromal cells and decidualized stromal cells: origins, transformation and functions. Gene 551 1–14. (https://doi.org/10.1016/j.gene.2014.08.047)
Zorena K, Jachimowicz-Duda O, Ślęzak D, et al. 2020 Adipokines and obesity. Potential link to metabolic disorders and chronic complications. Int J Mol Sci 21 3570. (https://doi.org/10.3390/ijms21103570)