Obesity in reproduction: Mechanisms from fertilization to post‑uterine development (Review)

Introduction

Obesity, defined by an excessive accumulation of body fat resulting from chronic nutrient overconsumption, has become a significant global public health issue, not only due to its high prevalence, but also due to its associated comorbidities and the resulting disruption of adipocyte-immune cell interactions within adipose tissue (1,2). As of 2016, ~650 million adults worldwide were classified as obese, with projections estimating that this number could reach four billion by the year 2035. In many developed nations, it is anticipated that nearly one-third of individuals will be affected in the coming years (3).

Obesity profoundly affects multiple organ systems through mechanisms involving oxidative stress, inflammation and metabolic dysregulation (4,5). Excessive nutrient intake leads to adipose tissue expansion and ectopic lipid accumulation, particularly in the liver, where it contributes to metabolic dysfunction-associated steatotic liver disease, characterized by mitochondrial dysfunction and the increased production of reactive oxygen species (ROS) (6-10). Oxidative stress promotes hepatocellular injury and inflammation, thereby advancing disease progression (11,12). In skeletal muscle, obesity promotes the accumulation of intermuscular and intramyocellular lipids, which impairs muscle regeneration and increases the risk of atrophy and sarcopenia through mechanisms of lipotoxicity (13,14). The brain is not spared; obesity leads to hypothalamic inflammation and gliosis, disrupting appetite regulation and energy homeostasis by impairing neuronal integrity in this critical region (15).

Moreover, obesity-induced chronic low-grade inflammation, mediated by adipose tissue macrophages and cytokines, exacerbates oxidative damage and disrupts metabolic homeostasis. These interconnected processes underlie the pathogenesis of metabolic syndrome, increasing cardiovascular risk and organ dysfunction. Thus, oxidative stress is a central mediator linking obesity to multisystemic metabolic disturbances (4,16,17).

Despite extensive research into the metabolic and cardiovascular complications of obesity, its effects on the reproductive system, particularly at the molecular and cellular levels, have received comparatively less attention. Recent evidence underscores that obesity profoundly disrupts reproductive health in both males and females, impairing gametogenesis, hormonal balance, fertilization, and subsequent embryonic and postnatal development (16,18,19). The mechanisms of these effects are multifactorial and include oxidative stress, altered steroidogenesis, disrupted endocrine signaling along the hypothalamic-pituitary-gonadal axis, mitochondrial dysfunction, epigenetic modifications and chronic inflammation (5,20-23). In females, obesity is associated with impaired oocyte quality, abnormal follicular environments, ovulatory dysfunction, and reduced implantation and live birth rates (18). In males, excess adiposity is associated with reduced sperm quality, altered hormone profiles, and increased sperm DNA damage, with evidence of intergenerational transmission of metabolic dysfunction mediated by epigenetic changes (24,25). Furthermore, obesity during pregnancy increases the risk of gestational complications, adversely affects placental function, and programs offspring for metabolic and reproductive disorders later in life (26). However, the field lacks comprehensive mechanistic frameworks that distinguish obesity-specific effects from those mediated by associated metabolic disorders or nutritional factors.

Despite these insights, a comprehensive review that synthesizes currently available knowledge on the mechanisms through which obesity affects the reproductive system from fertilization through post-uterine development remains lacking, at least to the best of our knowledge. The present review thus aimed to fill this gap by providing an integrative overview of the molecular mechanisms by which obesity impairs reproductive function, focusing on oxidative stress and its downstream effects at each stage, from gamete quality and fertilization to embryonic development and postnatal outcomes. By elucidating these pathways, it is hoped that the present review will inform future research and clinical strategies to mitigate the reproductive and developmental consequences of obesity.

Obesity as a driver of testicular inflammation

The male reproductive tract consists of multiple organs, including the testes, epididymis and prostate gland, which collectively enable sperm development and androgen production (27). Within the testes, spermatogenesis takes place inside seminiferous tubules lined by Sertoli cells. These cells support sperm maturation, uphold structural integrity, and establish the blood-testis barrier to protect developing germ cells from toxins and immune responses (28). Spermatogenesis progresses from spermatogonia through several developmental stages tightly regulated by testosterone and follicle-stimulating hormone (29-31). To study male reproduction, rodents that share comparable reproductive features and are frequently employed in reproductive studies (32,33) are used.

Obesity may compromise both sperm development and the blood-testis barrier through systemic inflammation, although exact pathways involved remain unclear. The present comprehensive overview discusses the complex association between obesity, particularly the accumulation of excess fatty acids and sugar, and signaling pathways involved in testicular development, as well as sperm maturation, motility, morphology and DNA integrity.

Diet-induced obesity and its impact on testicular function and hormonal regulation

Research utilizing high-fat diet (HFD) models to induce obesity has revealed significant effects of obesity on testicular function. A previous study which was performed as early as 2001 demonstrated that HFD-induced obesity increased the weight of the ventral prostate in Sprague-Dawley rats (34). It was the first-ever study to demonstrate a direct effect of obesity caused by saturated fat consumption on the reproductive tract, laying the groundwork for future research into how excess fat intake induced by obesity affects testicular function. Another notable study on Wistar rats aimed to evaluate the adaptive responses in the testes of adult rats treated with a non-toxic dose of the environmental chemical dichlorodiphenyldichloroethylene (DDE), either alone or in association with a HFD (35). That study concluded that HFD and DDE induce cellular stress, leading to antioxidant impairment, apoptosis and decreased levels of the androgen receptor (AR) and serum testosterone, all of which are associated with tissue damage. However, notable cellular proliferation was observed, considered an adaptive response to counterbalance tissue damage. Critical gaps exist in understanding how HFD-induced obesity specifically affects key regulatory pathways. Notably, a subsequent study examined the effect of both a HFD and exercise on the 'controller' of gonadal development, the KISS-1/G/G protein-coupled receptor 54 (GPR54) system, in the testes of growing rats (36). The increase of KISS-1/GPR54 during the testicular growing period, as measured using RT-qPCR and western blot analysis, was abolished by HFD feeding (36). Notably, that study also revealed that the regular testicular growing pattern, as well as normal KISS-1/GPR54 expression, can be restored through moderate-intensity aerobic exercise at 60-70% VO2 max (36). An interesting finding was reported in the study by Ma et al (37) regarding how zinc improves semen parameters in HFD-fed male rats by regulating the expression of long non-coding RNA (lncRNA) in testicular tissue.

Diet-induced reproductive dysfunction in males

While studies above focused on long-term HFD feeding, which induces obesity, the study by Falvo et al (38) examined the effects of short-term HFD feeding. They proved that HFD implementation as short as 5 weeks can reduce steroidogenesis, increase the apoptosis of spermatogenic cells, alter spermatogenesis with reduced protein levels of meiotic and post-meiotic markers, and notably compromise blood-testis barrier integrity through sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (NRF2)/mitogen-activated protein kinase (MAPK) signaling pathways (38). Moreover, a high-fat, vitamin D-deficient diet in Sprague-Dawley rats has been shown to reduce sperm motility, mitochondrial function and fertilizing capacity (39).

Obesity, characterized by the excess accumulation of free fatty acids and glucose in blood and cells, is known to elevate ROS production (40). Multiple animal studies have confirmed that, for instance, HFD triggers the accumulation of ROS in sperm and testicular tissue, thereby leading to reproductive impairment. For example, a study using an animal model of HFD demonstrated that HFD-fed mice displayed a decline in the levels of antioxidant enzymes, such as glutathione peroxidase (GPX), catalase and superoxide dismutase (SOD), in testicular and epididymal tissues compared to mice fed a control diet (41). In line with this finding, mature sperm in HFD-fed mice exhibited higher ROS levels and decreased levels of GPX1 protein, resulting in impaired mitochondrial structural integrity and reduced mitochondrial membrane potential, as well as decreased ATP production. Notably, considering the significant impairment of mitochondrial function, sperm motility was found to be reduced. Additionally, the same conclusions were found to be true for obese males in the scope of the study (41).

Another study examined the obesity-related increase in intestinal permeability, which allows the passage of intestinal bacteria into the circulation, known as metabolic endotoxemia (ME) (42). That study on 37 infertile males revealed an association between obesity-related ME, measured as serum zonulin, and impaired sperm DNA integrity. The association was found to be persistent even after adjusting for confounding factors, such as age and duration of abstinence. However, the exact molecular mechanisms involved were not discussed (42). The key findings of the study by Bakos et al (43) on C57/Bl6 male mice fed a HFD were that obesity significantly decreased the percentage of motile spermatozoa (36 vs. 44% in controls) and that this reduction in motility was associated with altered energy metabolism and increased redox imbalance in sperm cells. The study by Han et al (44) reached the same conclusions by observing abnormal testicular structures on a larger scale and detecting excessive oxidative stress, as well as enhanced apoptosis and impaired glucose metabolism markers, on a molecular scale.

The impact of obesity on the male reproductive system has been observed from another perspective through the use of high-sugar mouse models, thereby mimicking metabolic syndrome (MetS). The key finding of the study by Rahali et al (45) was that MetS induces severe testicular toxicity in male rats, as measured by BAX downregulation, BCL2 upregulation and a decreased testosterone level, which was associated with the downregulation of cytochrome P450 family (CYP)11A1, CYP17A1 and 17β HSD testicular markers. In another study, hypercholesterolemic rabbits, fed a diet supplemented with 0.05% cholesterol, concluded that excess cholesterol leads to a reduced semen volume and sperm motility, as well as changes in sperm morphology (head and flagellum) (46). The additional impact of obesity on the human and rodent male reproductive systems is presented in Table I.

Table I Effects of obesity on the human and rodent male reproductive systems.

Table I

Effects of obesity on the human and rodent male reproductive systems.

Model	Treatment	Effect	(Refs.)
Sprague-Dawley rats	16-week HFD	↓ Testosterone synthesis ↑ Spermatogenic cell apoptosis	(57)
Ldlr−/− Leiden	24-week HFD + BA administration	↑ Plasma leptin abnormal testosterone levels aberrant ITO ↑ Level of tubules in stages VII/VIII	(58)
Rats with STz-NA-induced diabetes	HFD until 12 weeks of age	↓ Epididymal sperm motility ↓ Histone-protamine transition ↓ Plasma testosterone ↓ Sperm count	(59)
Wistar rats	4-week HFD	↓ Epididymal sperm maturationas ↓ Testosterone levels ↓ Sperm viability ↓ Capacitation	(60)
C57BL/6 mice	8-week HFD + diet reversal	disrupted testicular BTB integrity ↑ levels of oxidative stress abnormal expression of BTB-related proteins	(61)
C57Bl/6 mice AdipoR1 KO mice Akita mice	28-week HFD (C57Bl/6) and standard chow (AdipoR1 KO, Akita)	↓ Sperm count, motility fertilizing ability and AdipoR1 gene and protein (in HFD) ↑ Pro-apoptotic genes and poteins (in HFD) ↓ Testes weight, sperm count, motility, and fertilizing ability, phosphorylation of AMPK (in AdipoR1 KO) ↑ Pro-apoptotic proteins, CASP6 activity and pathologically apoptotic seminiferous tubules (in AdipoR1 KO)	(62)
C57BL/6J mice	10-week HFD + exercise	↓ LEP-JAK-STAT pathway ↓ Expression of SF-1, StAR, CYP11A1 ↓ Sserum testosterone-to-estradiol ratio, sperm quality effect can be reversed by exercise	(63)
Wistar rats	16-week HFD	↓ Male fertility, fertilization, cell adhesion genes ↑ Obesity, lipid metabolism-related, immune response-related and CYP genes ↑ Aromatase activity	(64)
Wistar rats	38-week hyperglycidic diet	15 Proteins with differential abundance	(65)

[i] Ldlr^−/− Leiden, low-density lipoprotein receptor knockout Leiden; HFD, high-fat diet; STz-NA, streptozotocin-nicotinamide; ITO, intra-tubular organisation; BTB, blood-testis barrier; AdipoR1, Adiponectin receptor 1; SF-1, steroidogenic factor-1; StAR, steroidogenic acute regulatory protein; CYP11A1; P-450 side-chain cleavage enzyme; CASP6, caspase 6; AMPK, AMP-activated protein kinase; LEP-JAK-STAT, leptin-Janus kinase-signal transducer and activator of transcription.

On the other hand, the relation of obesity to testicular cancer (TC) appears to be heterogeneous. For instance, tentative evidence of an inverse association between body mass index (BMI) and testicular germ-cell tumors (TGCT) was provided in a previous meta-analysis (47). Additionally, a Norwegian study found that the risk of developing TC decreased with adult BMI (48). On the other hand, a high BMI was more prevalent in TGCT cases than in the control group, according to Dieckmann et al (49). In a study on Canadian males, it was demonstrated that a high dairy, particularly cheese, intake was associated with an elevated risk of developing TC (50). Considering that body fat composition serves as a more effective indicator of obesity than BMI, in another study, computed tomography was used to determine visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and skeletal muscle area ratios, as well as TC stage (51). That study determined a statistically significant moderate positive association between testicular tumor stage and the VAT/SAT ratio. While this topic requires further assessment, an interesting finding was reported in the study by Puri et al (52), who stated that the connection between TC and obesity was bidirectional. More specifically, it appears that TC survivors are at an increased risk of metabolic syndrome and obesity development.

While several studies have assessed the impact of obesity on testicular tissue and sperm, only a small number of studies have examined the potential for reversing its effects. A recent study claimed that micronutrient-based antioxidant intervention, containing added folate, vitamin B6, choline, betaine and zinc in rats can ameliorate the effects of a HFD on testicular tissue (53). Briefly, at 30.5 weeks of post-weaning HFD, sperm was harvested and analyzed for sperm count and 8-hydroxy-2'-deoxyguanosine (8-OHdG) content and testes were analyzed for 8-OhdG, malondialdehyde, folate and glutathione content, the activity of SOD, catalase and GPX, susceptibility index of pro-oxidative damage and mRNA the expression of Nrf2, NFκB-p65, interleukin (IL)-6 and IL-10, and Tnfa. Notably, micronutrient-based antioxidant intervention in HFD significantly mitigated HFD-induced sperm and testicular oxidative damage by enhancing testicular antioxidant capacity through the regulation of the parameters above (53). Subsequently, Suleiman et al (54) demonstrated the therapeutic potential of bee bread, the outcome of the fermentation from the combination of pollen, digestive enzymes found in saliva and nectar, on obesity-induced testicular-derived oxidative stress, inflammation and apoptosis in rats fed a HFD (54). They demonstrated that administering bee bread in combination with a HFD diminished the detrimental effects of a HFD, including a decrease in antioxidant enzymes and proliferating cell nuclear antigen immunostaining, as well as an increase in inflammation and apoptosis markers (e.g., cleaved caspase-3) in the testes (54). Additional research has demonstrated the ameliorative effects of Myrtus communis L. extract on HFD-induced damage to the testes in rats, through the inhibition of oxidative stress (55). In another study, to assess whether physical exercise can effectively ameliorate obesity-induced abnormalities in male fertility, the sperm parameters (motility, concentration, the ability to undergo capacitation and the acrosome reaction) of HFD-fed mice that underwent physical labor were evaluated (56). That study provided evidence that the adverse effects of obesity can be mitigated through physical exercise. Additionally, that study identified several small non-coding RNAs, particularly microRNAs (miRNAs/miRs; miR-6538, miR-129-1, miR-7b, miR-196a-1, miR-872, miR-21a, miR-143 and miR-200a), in germ cells that may play a crucial role in the effects of obesity and physical exercise on spermatozoa (56).

In summary, data unequivocally suggest that excessive fat and sugar intake exert disruptive effects on all aspects of male reproduction, including sperm maturation, mitochondrial structure and function, oxidative stress levels, and sperm motility in both humans and rodent obesity models. However, several reports claim that normal testicular function can be restored through physical exercise and therapeutic intervention.

Metabolic syndrome: Molecular pathways linking MetS to male infertility

MetS is characterized by a group of conditions, including insulin resistance, dyslipidemia, hypertension and chronic low-grade inflammation. Beyond obesity alone, MetS exerts significant detrimental effects on male fertility. Insulin resistance disrupts insulin signaling pathways that are critical for testosterone biosynthesis in Leydig cells. This leads to hypogonadism and decreased support for spermatogenesis (66). Dyslipidemia promotes lipid peroxidation in sperm membranes, compromising motility and acrosomal function. Moreover, hypertension-induced endothelial dysfunction reduces testicular perfusion, exacerbating oxidative stress and hypoxia (67). Chronic inflammation, driven by cytokines, such as TNF-α and IL-6 secreted from adipose tissue, disrupts the blood-testis barrier. This occurs through the activation of the MAPK and NF-κB signaling pathways, enabling immune cell infiltration. Subsequently, germ cell apoptosis also becomes increased (66,67).

Metabolic syndrome also alters adipokine profiles. Elevated leptin (hyperleptinemia) and reduced adiponectin levels negatively affect the hypothalamic-pituitary-gonadal axis. This impairment further decreases testosterone production and spermatogenesis (68). Emerging evidence also implicates epigenetic modifications in sperm from males with MetS, including aberrant DNA methylation and histone acetylation patterns, which may contribute to the transgenerational transmission of metabolic and reproductive dysfunction (66). Collectively, these metabolic and molecular alterations underscore the critical role of MetS in male infertility and highlight the need for integrated clinical approaches targeting metabolic health to improve reproductive outcomes.

Obesity as a driver of ovarian dysfunction and female reproductive impairment

Located within the pelvis and supported by ligaments, the female reproductive system consists of internal organs (the ovaries, fallopian tubes, uterus, cervix and vagina), as well as external genitalia (69,70). The ovaries lie adjacent to the uterus and fimbriae and act as the site of oocyte development and maturation (70). Apart from producing eggs, they release estrogen and progesterone to regulate the menstrual cycle and pregnancy. The fallopian tubes carry the oocyte to the uterus and typically serve as the site of fertilization; these tubes are segmented into fimbria, infundibulum, ampulla, and isthmus (71). The muscular uterus supports implantation and fetal growth (72).

Obesity has been proven to have marked effect on female reproduction; it has been reported that obesity promotes lipid accumulation and morphological changes across the uterus, ovary and oviduct, with increased NF-κB and MAPK signaling (73). Additionally, obesity alters the immune cell profile in reproductive tissues, as detailed by St-Germain et al (74).

The present comprehensive overview discusses the mechanistic links between obesity, particularly the accumulation of excess fatty acids and glucose, and the disruption of signaling pathways in ovarian folliculogenesis, steroidogenesis and oocyte quality.

Metabolic stress and follicular development disruption induced by a high-fat diet

A pivotal study from 2014 demonstrated that progressive obesity in female mice altered ovarian steroidogenic enzymes and inflammatory pathways, with NF-κB signaling elevated by 12 weeks of age and STAR protein levels reduced by 50% after 24 weeks of exposure to a HFD (75). That foundational study revealed temporal shifts in CYP11A1 and CYP19A1 expression, impairing estrogen synthesis and follicular survival (75). Building on this, a study in 2015 demonstrated that hyperglycemic conditions during oocyte maturation increase ROS by 40% and reduce developmental competence in antral follicle-derived oocytes, despite normal growth during earlier follicular stages (76). A landmark study in 2016 established that a HFD directly reduces primordial follicle reserves by 32% in mice through ovarian macrophage infiltration and systemic inflammation, independent of obesity phenotype, while compromising long-term fertility outcomes (77).

Lipotoxicity, oxidative stress, and mitochondrial dysfunction in ovarian cells

Exposure to a HFD induces lipotoxic stress in ovarian cells, disrupting the follicular microenvironment and compromising oocyte developmental competence. Wu et al (78) demonstrated that HFD-fed mice exhibited lipid accumulation in cumulus-oocyte complexes, leading to oxidative stress (elevated ROS levels) and endoplasmic reticulum stress markers (BiP/GRP78), which impaired fertilization rates by 35% compared to the controls. Single-cell RNA sequencing by Zhu et al (79) revealed that HFD altered mitochondrial respiration pathways in oocytes, resulting in the downregulation of Ppargc1a (a key regulator of mitochondrial biogenesis) and disrupted metabolic coupling between granulosa cells and oocytes, which led to delayed embryo cleavage and reduced blastocyst formation. These defects were associated with aberrant lipid metabolism in granulosa cells, including the upregulation of fatty acid-binding protein 4 and the dysregulation of cholesterol homeostasis (79).

Interventional studies have highlighted potential therapeutic strategies. Choi et al (80) demonstrated that high-molecular-weight chitosan supplementation in HFD-fed mice reduced ovarian lipid droplets by 40% and restored ovulation rates through improved insulin sensitivity and AMPK activation. Similarly, Morimoto et al (81) identified HFD-induced glycolytic disruptions in granulosa cells, characterized by reduced Hk2 and Pfkfb3 expression, which impairs pyruvate provision to oocytes, a critical energy substrate for maturation. This metabolic uncoupling was exacerbated in aged obese mice, where oocytes displayed 50% lower ATP levels and increased aneuploidy rates. These findings underscore that HFD-induced lipotoxicity in ovarian cells disrupts structural and functional integrity at multiple levels, from follicular communication to embryonic viability, with redox imbalance and mitochondrial dysfunction as central mechanisms (81).

Hormonal imbalance, inflammation and fertility outcomes in obese females

Recent evidence suggests that HFD-induced oxidative stress disrupts the ovarian microenvironment by impairing oocyte mitochondrial function, thereby accelerating follicular atresia through ROS-mediated DNA damage (82). These effects are compounded by hypothalamic-pituitary-ovarian axis dysregulation, in which obese women exhibit a 25% lower luteinizing hormone (LH) pulse amplitude and elevated insulin levels that disrupt gonadotropin signaling (83). Notably, interventions show promise: A study published in 2024 identified that antioxidant-rich diets containing phytonutrients and organosulfur compounds can mitigate 68% of HFD-induced ovulation irregularities by restoring hormonal balance (82). Concurrently, lifestyle modifications combining Mediterranean-style diets with moderate-intensity exercise (45-60% VO2max) improve pregnancy rates in obese women by enhancing insulin sensitivity and reducing inflammatory cytokines (84).

Studies on animals have demonstrated that female rodents fed a HFD exhibit reduced ovarian antioxidant enzyme activity, resulting in oocyte mitochondrial dysfunction. This oxidative damage disrupts ATP production and induces lipid peroxidation in granulosa cells, impairing follicular development. Studies on humans corroborate these findings, demonstrating elevated ROS levels in the follicular fluid of obese women undergoing fertility treatments, which are associated with reduced oocyte maturation rates and embryo quality (85-87).

The inflammatory milieu in obesity further exacerbates redox imbalance through adipose-derived cytokines, such as TNF-α and IL-6, which activate signaling pathways promoting granulosa cell apoptosis (87). A previous systematic review demonstrated that obese women with elevated chemerin levels faced a 2.3-fold higher risk of anovulatory cycles. Structural analyses of ovarian tissue from HFD-fed mice exhibit a reduction in primordial follicle reserves and stromal lipid accumulation, paralleled by downregulation of enzymes essential for estrogen synthesis. Additionally, dysregulated adipokines, such as leptin and adiponectin, alter GnRH pulsatility, reducing LH and FSH secretion and further compromising ovulation. This hormonal imbalance contributes to menstrual irregularities, anovulation, and infertility (87). Moreover, obesity-related alterations in adipokine levels exacerbate insulin resistance and promote systemic inflammation, further disrupting ovarian function and impairing folliculogenesis (88). A summary of molecular mechanisms caused by obesity in both females and males is illustrated in Fig. 1.

Figure 1 Schematic illustration of the effects of obesity on male and female reproductive systems. On the left panel, male obesity is proven to have a significant impact on the development of normal sperm, thereby causing reduced motility sperm and atypical sperm production. On the right panel, female obesity is proven to cause altered ovarian morphology and increased cytoplasmic lipid accumulation in oocytes. Further effects of obesity in both female and male reproductive system physiology and development are indicated as a downward-looking arrow (decrease) and an upward-looking arrow (increase). NS, normal sperm; RMS, reduced motility sperm; atypical sperm; ILCA, increased cytoplasmic lipid accumulation; BTB, blood-testis barrier; KISS-1, KiSS-1 metastasis suppressor; GPR54, G protein-coupled receptor 54; AR, androgen receptor; SIRT1, sirtuin 1; NRF2, nuclear factor erythroid 2-related factor 2; MMP, mitochondrial membrane potential; ATP, adenosine triphosphate; StAR, steroidogenic acute regulatory protein; CYP11A1, cytochrome P450 family 11 subfamily A member 1; GPX, glutathione peroxidase; SOD, superoxide dismutase; ROS, reactive oxygen species; CASP3, caspase 3; BAX, BCL2-associated X protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; MAPK, mitogen-activated protein kinase; 8-OHdG, 8-hydroxy-2'-deoxyguanosine; PCOS, polycystic ovary syndrome; ICLA, in vitro cultured large antral follicle; Ppargc1a, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ER, endoplasmic reticulum; COCs, cumulus-oocyte complexes; LH, luteinizing hormone; FSH, follicle-stimulating hormone.

Epidemiological research has reported that women with obesity have a 2.7-fold increased risk of infertility and a 25-37% higher risk of miscarriage compared to women of normal weight (89). Obesity also worsens the clinical and metabolic manifestations of polycystic ovary syndrome (PCOS), a leading cause of female infertility, by promoting hyperinsulinemia and hyperandrogenism, which impair follicular development and ovulatory function. Additionally, obesity negatively affects assisted reproductive technology (ART), reducing pregnancy and live birth rates, and increasing the likelihood of ART failure (90,91). The additional impact of obesity on the human and rodent female reproductive systems is presented in Table II.

Table II Effects of obesity on the human and rodent female reproductive systems.

Table II

Effects of obesity on the human and rodent female reproductive systems.

Model	Treatment/intervention	Effect	(Refs.)
CBA mice	4-week HFD	Lipid accumulation in COCs ↑ ROS, ↑ ER stress ↓ Fertilization rates (35%)	(78)
C57BL/6 mice	Single-cell RNA-seq + HFD	↓ Ppargc1a (mitochondrial biogenesis) impaired glucolipid metabolism delayed embryo cleavage ↓ Follicle number	(96)
B6C3F1 mice	4-week HFD + WSC	↓ Ovarian lipid droplets (40%) restored ovulation via AMPK activation	(80)
C57BL/6J mice	HFD + aged cohorts	↓ Granulosa cell Hk2/Pfkfb3 ↓ Oocyte ATP (50%) ↑ Aneuploidy	(60)
Women (clinical)	Obesity (BMI ≥30)	↓ Follicular fluid quality ↑ ROS ↓ Oocyte maturation ↓ Embryo quality	(78)
C57BL/6J mice	Maternal HFD (preconception)	Altered mitochondrial membrane potential (↓ΔΨm) in oocytes/zygotes ↑ ROS	(97)
Women (PCOS)	Obesity	↓ Menstrual regularity ↑ Androgen levels Suppressed ovulation Effect can be reversed by metformin	(98)

[i] HFD, high-fat diet; COCs, cumulus-oocyte complexes; ROS, reactive oxygen species; ER, endoplasmic reticulum; scRNA-seq, single-cell RNA sequencing; Ppargc1a, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; WSC, water-soluble chitosan; AMPK, AMP-activated protein kinase; GC, granulosa cells; Hk2, Hhexokinase 2; Pfkfb3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; ATP, adenosine triphosphate; ΔΨm, mitochondrial membrane potential; PCOS, polycystic ovary syndrome; BMI, body mass index.

Apart from the physiological impact on the uterus and ovaries, obesity increases the risk of developing endometrial cancer, which can be decreased through weight loss by recruiting protective immune cell types to the endometrium (92). Additionally, obesity influences DNA methylation in pre-symptomatic endometrial epithelial cells, and the persistent dysregulation of DNA methylation in obese women may contribute to the development of endometrial cancer (93).

Weight loss through lifestyle modifications, pharmacological intervention, or bariatric surgery has been shown to improve menstrual regularity, reduce androgen levels, enhance ovulation and increase spontaneous pregnancy rates in obese women. These improvements underscore the importance of addressing obesity as a modifiable risk factor to restore reproductive potential (94,95).

In summary, substantial evidence suggests that the excessive consumption of fats and sugars has a detrimental effect on various aspects of female reproductive health. This includes ovarian folliculogenesis, steroid hormone production, oxidative balance and oocyte quality. These disruptions are consistently observed in both human studies and animal models of obesity, emphasizing the significant effects of metabolic dysregulation on female fertility. Recent research suggests that lifestyle changes, such as moderate-intensity exercise and targeted therapeutic interventions like antioxidant supplementation, may help reduce these harmful effects and restore normal ovarian function. These findings highlight the importance of comprehensive strategies to address obesity-related reproductive dysfunction in women.

Fertilization capacity as an indicator of metabolic health

Placental development and physiology. Fertilization is initiated when a sperm penetrates the zona pellucida of an egg, forming a zygote. This process requires viable gametes, accurate sperm transport, capacitation, hyperactivation, acrosome reaction and membrane fusion (99-104). Precise pH, calcium signaling, hormones, enzymatic activity and molecular recognition all coordinate fertilization (104-106).

Initial connections between obesity and fertilization emerged through the introduction and development of in vitro fertilization (IVF). In 2011, researchers noted that both PCOS and maternal obesity affected oocyte size in IVF/intracytoplasmic sperm injection cycles, thereby establishing the direct impact of metabolic health on gamete quality (100). Considering that the mitochondria play vital roles in oocyte function, it is evident that mitochondrial functionality is a direct indicator of oocyte quality, which in turn affects fertilization potential and development into viable offspring (107). In this context, a previous retrospective study explored the effects of overweight and obesity on the IVF outcomes of poor ovarian responders (PORs) (108). A total of 188 PORs undergoing IVF cycles were stratified into three groups (normal weight PORs, overweight PORs and obese PORs), where it was concluded that obese PORs had decreased fertilization and clinical pregnancy rates. In another study, the proteomic assessment of follicular fluid from women undergoing IVF using liquid chromatography-mass spectrometry analysis found 25 proteins to be significantly altered in the follicular fluid from women with obesity (109).

Molecular and cellular mechanisms linking obesity to impaired fertilization

From a molecular perspective, obesity impairs sperm function. HFD-fed male mice demonstrate reduced sperm-oocyte binding ability, indicating impaired sperm recognition (43). In another study, HFD exposure was shown to decrease testicular estradiol, the E2-to-testosterone ratio and the levels of critical fatty acids, such as docosahexaenoic acid, leading to premature acrosomal exocytosis and diminished fertilization capacity (110). In the context of fatty acid-related sperm modulation, Cooray et al (111) extrapolated that polyunsaturated FAs (PUFAs), more specifically ω-3 unsaturated fatty acids, have the highest potency in modulating sperm ion channels to increase sperm motility, which might indicate higher fertilization potential (111). In another study, to identify a molecular marker for reduced fertilization rates caused by obesity, screening for changes in gene expression in the male reproductive tract revealed a decreased cysteine-rich secretory protein 4 (CRISP4) expression in the testis and epididymis of obese mice (112). The importance of CRISPR was confirmed when the same study successfully improved the fertilization rate through CRISPR treatment of sperm from HFD mice prior to in vitro fertilization. Another potential player in obesity-related fertilization issues appears to be an inflammatory marker named lipocalin 2, which remains to be explored in the reproductive tracts of both females and males (113). Research on other species supports these findings: Bulls on high-gain diets produce semen with reduced blastocyst formation capacity following IVF, linked to increased necrosis and acrosome damage (114). Similarly, rats on high-fat, vitamin D-deficient diets have been shown to exhibit decreased sperm motility and mitochondrial dysfunction, impairing fertilizing ability (39). In females, obesity-associated implantation failure is associated with an altered uterine DNA methylation and a reduced Dnmt gene expression (115).

By contrast, an intergenerational murine model combining regular chow with a high-energy supplement indicated that an overweight status was associated with higher ovulation rates and the increased development of fertilized oocytes, although embryo quality was poor (113,116).

Dependence of in utero development on parental obesity

Impact of maternal obesity on placental function and fetal organ development. The placenta is an essential organ for normal in utero development in mammals, functioning as the critical exchange site for nutrients, gases, and waste products between mother and fetus (117). This transitory organ also serves endocrine functions by producing hormones necessary for maintaining pregnancy and regulating fetal growth. Considering the established connection with the maternal blood supply, it is no wonder that maternal obesity influences the in utero development of fetal organ systems through the placenta (118).

The placenta itself is affected by maternal obesity, with its effects being observable through changes in placental morphology, metabolism, inflammation, oxidative state, endothelial function and altered angiogenesis (119,120). Moreover, a previous study concluded that human placentas exhibit sex-specific adaptive changes in response to maternal obesity (121). Placental development and function in a mouse model of diet-induced obesity were proven to be impaired through the altered transcriptome of placenta progenitor cells in the preimplantation (trophectoderm) and early post-implantation (ectoplacental cone) placenta precursors (121). Crucially, the differential expression of major upstream transcriptional regulators in developmental pathways, such as Wingless-related integration site (Wnt) signaling, p38 MAPK, ERK and Toll-like receptor 2 signaling, was found to be impaired (121). In line with this, uterine natural killer cells, which play essential roles in coordinating uterine angiogenesis and promoting maternal tolerance to fetal tissue, were found to display an altered repertoire of natural killer receptors (inhibitory KIR2DL1 and activating KIR2DS1 receptors), thereby impacting early developmental processes (122). Similarly, a study using a cohort of obese or lean women found that obesity leads to a significant reduction in natural killer cell numbers, accompanied by impaired uterine artery remodeling, potentially influencing further fetal development (123). A murine study found that obesity alters the mouse endometrial transcriptome, potentially affecting the endometrium's ability to function during pregnancy (124).

To assess the impact of placental and endometrial changes identified in the aforementioned studies on fetal development, several studies were conducted. Ford et al (125) followed fetal pancreatic development in a sheep model of obesity. They noted that, although all organs were heavier in fetuses from obesogenic (OB) ewes, only the pancreatic weight increased as a percentage of fetal weight (125). This was accompanied by 50% more insulin-positive cells per unit of pancreatic area in fetuses from OB ewes, as well as the notion that obesity accelerates fetal pancreatic beta-cell, but not alpha-cell, development (122).

The muscular system has also been found to be affected by maternal obesity and exposure to excessive glucocorticoids (126). Specifically, glucocorticoid exposure in embryonic and fetal developmental stages has emerged as a cause of cardiovascular disease and muscle atrophy in adulthood. Previous studies even mention obesity-related epigenetic dysregulation in Prader-Willi syndrome and the agouti gene (127,128). An interesting study examining gut intestinal structure and placental vascularization found that diet-induced obesity decreased the maternal intestinal levels of short-chain fatty acids and their receptors, impaired gut barrier integrity, and was associated with fetal intestinal inflammation (129). Moreover, maternal obesity during pregnancy has been shown to upregulate the insulin signaling genes, IRS2, PIK3CB and SREBP1c, in skeletal muscle and perirenal fat, thereby favoring insulin sensitivity (130).

Notably, the results of a study performed on baboon fetuses of obese baboon mothers who consumed a high-sugar, HFD during pregnancy demonstrated that the fetuses developed a fatty liver along with significant metabolic disruption in the liver (131). Most notably, fetal livers exhibited the dysregulation of the tricarboxylic acid cycle, proteasome, oxidative phosphorylation, glycolysis and the Wnt/β-catenin signaling pathway, one of the most critical developmental signaling pathways, accompanied by marked lipid accumulation (131). Another study on baboons proved how maternal obesity affects fetal liver androgen signaling through reduced CYP2b6 and CYP3A activity in conjunction with decreased nuclear AR-45 expression. Notably, the effect was proven to be sex-specific, affecting only males (132).

Several studies have provided evidence of maternal obesity-related impairment of kidney development (133,134). For instance, Zhou et al (133) found a decreased number of peroxisomes and an increase in inflammasomes, resulting in pyroptosis and apoptosis in the fetal kidney of obese mothers. Additionally, the Gomeroi Gaaynggal study discovered that children born to obese mothers had a reduced kidney size relative to estimated fetal weight, suggesting a degree of glomerular hyperfiltration in utero (134). The study by Tain et al (135) demonstrated that maternal high-fructose intake causes programmed hypertension in offspring through changes in the renal transcriptome.

Epigenetic and molecular mechanisms linking maternal obesity to long-term offspring health

Emerging evidence also highlights the disruption of fetal oocyte development by maternal obesity. The recent stud by Tang et al (136) demonstrated that obesity induced meiotic defects in fetal oocytes, including synapsis abnormalities and increased aneuploidy rates, alongside the epigenetic dysregulation of DNA methylation and histone modifications at critical developmental genes, such as Stra8 and Sycp3. These alterations were linked to oxidative stress and impaired DNA repair mechanisms, suggesting a direct intergenerational transmission of metabolic risks to reproductive health (136).

Currently, there is limited research available investigating whether maternal or paternal obesity directly contributes to the occurrence of chromosomal abnormalities in offspring, highlighting a significant gap in understanding the parental origins of such genetic risks.

A previous study on obesity has brought epigenetic mechanisms, including DNA methylation, histone modifications and miRNAs into focus during pregnancy as a significant indicator of disease susceptibility in later stages of human life (137). To combat the effects of obesity on in utero development, the assessment of alternate-day fasting (ADF) and time-restricted feeding (TRF) in obese pregnant mice found contrasting effects on placental function and fetal development. TRF was proven to be superior to ADF, as it enhanced placental nutrient transport and fetal development by reducing endoplasmic reticulum stress and inflammatory responses (138).

There is no doubt that parental obesity is a critical indicator of impaired fetal development. The current findings are summarized in Fig. 2. However, there is still room to further explore the molecular effects of either paternal or maternal obesity on specific organic systems.

Figure 2 Schematic illustration of the mechanistic pathways by which maternal obesity influences fetal development via placental alterations. On the left panel, maternal obesity is associated with increased circulating levels of pro-inflammatory cytokines (IL-6, TNF-α), FFAs and glucose. Apart from the increase in pro-inflammatory markers, altered placental morphology, impaired angiogenesis, and increased oxidative stress can also be observed. Importantly, deregulated placental signaling pathways, including Wnt, ERK, and TLR2, as well as the activation of NF-κB, collectively disrupt placental function. On the right panel, these placental changes adversely impact multiple fetal organ system development processes. The fetal liver exhibits lipid accumulation and impaired TCA cycle activity. The pancreas shows enlargement and accelerated BC development. The kidney exhibits a reduced size and a decreased number of peroxisomes. The brain is affected through altered hypothalamic and hippocampal development. In addition, epigenetic modifications, such as altered methylation patterns, which may program long-term disease susceptibility, are caused by parental obesity. Fetal muscle is shown to have an increased risk of atrophy and predisposition to cardiovascular disease. Together, these pathways underscore the multifaceted effects of maternal obesity on in utero development and future offspring health. IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; FFA, free fatty acids; TCA, tricarboxylic acid; Wnt, wingless-related integration site; ERK, extracellular signal-regulated kinase; TLR2, Toll-like receptor 2; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; BC, beta cell; PEX, peroxisome.

Obesity and offspring

Research and mechanisms linking parental obesity to offspring health. The association between maternal or paternal obesity and health outcomes of the offspring has emerged as a critical area of research over the past several decades.

In the early 90s, research focused on the outcomes of pregnancy. For instance, a previous study in 1990 reported that the perinatal mortality rate increased from 37 to 121 per 1,000 in obese women, indicating that even since then, it was proven that obese women were more likely to undergo premature labor with a negative outcome (139). Nevertheless, mechanistic insight as to what causes specific pregnancy outcomes and further offspring development did not lack behind. A study on amniotic fluid at 32 to 38 weeks of gestation revealed that insulin levels at that time account for a longitudinal correlation with relative obesity in children at the age of 6 (140). That study suggested that premature and excessive exposure to insulin during gestation may predispose to obesity in childhood. In line withthis finding, another study in 2005 provided evidence that children who are large for gestational age at birth and exposed to an intrauterine environment of either diabetes or maternal obesity are at an increased risk of developing metabolic syndrome (141).

Recent studies have focused on the signaling pathways involved in the effects of maternal obesity on the offspring. The study by Moeckli et al (142) discovered that pathways involved in metabolism (e.g., liver-related genes such as Egfr, Vegfb, Wnt2 and Pparg), the innate immune system, the clotting cascade and the cell cycle were consistently dysregulated in the offspring of obese mothers. Notably, female offspring exhibited higher non-alcoholic liver disease prevalence, while males exhibited increased fibrosis, indicating the different effects of the obese mother based on offspring sex (142). Furthermore, a review article provided a detailed explanation of how maternal obesity affects hypothalamic development and later function (143). Accordingly, another review article in addressed the emerging role of the hypothalamus in metabolic regulation in offspring of mothers with maternal obesity (144). The analysis of data from two French birth cohorts, EDEN (encompassing all gestational ages) and EPIPAGE-2 (preterm children born between 24 and 34 weeks of gestation), revealed the impact of maternal obesity on the cognitive development of children. In both cohorts, pre-pregnancy obesity was associated with lower verbal intelligence quotient (IQ) domains, resulting in lower IQ scores at 5 years (145).

Sertorio et al (146) provided further knowledge on the topic of the health implications of parental high-fat, high-sugar diet intake on male offspring. Their study conducted on rats evaluated multiple markers, including serum levels of testosterone and FSH, testicular gene expression of steroidogenic enzymes, epigenetic and inflammatory markers, as well as daily sperm production, sperm transit time and sperm morphology (146). Of note, several factors were influenced only by one parent: Maternal diet affected cytokine production, testicular epigenetic parameters, inflammatory response, oxidative balance and daily sperm production, while serum testosterone levels were affected by the paternal diet (146). Furthermore, another study found that cognitive deficits and impaired sphingolipid metabolism were induced in offspring through both the maternal and paternal lineages (147).

Epigenetic, cognitive and metabolic impacts of parental obesity

Notably, a subsequent study of methylation profiles of genome-wide CpG sites in blood samples from a pediatric longitudinal cohort revealed the influence of the weight of mothers on the methylome of offspring (148). Briefly, abundant DNA methylation changes during child development from birth to 6 months were detected in addition to DNA methylation biomarkers that could discriminate children born to mothers who suffered from obesity or obesity with gestational diabetes (148). Furthermore, another study aimed to elucidate the effects of maternal obesity on offspring in Kawasaki disease-like vasculitis and the underlying mechanisms (149). The data of that study demonstrated that maternal obesity led to more severe vasculitis and induces altered cardiac structure in the offspring, and also promoted the expression of pro-inflammatory cytokines through the activation of the NF-κB signaling pathway (149). Maternal obesity during pregnancy was recently connected to reduced hippocampal ephrin-A3/EphA4 signaling in adult mouse offspring, thereby impairing synaptic plasticity and gliovascular unit integrity, with microglial activation indicating neuroinflammation (150). In 2024, Nelson and Friedman (151) summarized the immense impact of a maternal Western-style diet on the programming of the fetal immune system.

Conversely, paternal obesity has been shown to have a significant effect on the cognitive functions of offspring in murine models. The underlying mechanism involves sperm-derived methylation of the brain-derived neurotrophic factor (BDNF) gene promoter, which disrupts BDNF/tyrosine receptor kinase B signaling (132). Another study demonstrated that offspring fertility appeared to be influenced by paternal obesity, indicating that paternal obesity can span multiple generations (152). Evidence from that study demonstrated a transgenerational increase in methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit and Wilms tumor protein N6-methyladenosine levels in the testes of offspring mice, indicating an epigenetic mechanism. Previous studies have addressed the significant impact of paternal obesity on offspring metabolism (153,154). Notably, female offspring of an obese father display impaired gluconeogenesis clues caused by sperm-transmitted methylation of the insulin-like growth factor (IGF)2/H19 imprinting control region in the liver of offspring, inducing enhanced gluconeogenesis and an elevated expression of key gluconeogenesis enzyme phosphoenolpyruvate carboxykinase (154). Another mechanism of transgenerational metabolic dysfunction induction was found to be sperm H3K27me3-dependent epigenetic regulation of glucose metabolism and apoptosis (155). Of note, only mild, transient metabolic changes were observed in the early life of offspring in a sperm chromatin accessibility study, indicating that the developmental compensatory mechanisms of the offspring can counteract epigenetic inheritance (156). To establish the role of paternal caloric restriction (CR) preconception, researchers discovered that the offspring display attenuated AMPK/SIRT1 pathway (associated with inflammation and oxidative stress), indicating beneficial effects of paternal CR (157). Furthermore, another case-control study found that the risk of congenital urogenital anomalies increased with paternal BMI during the preconception period (158). Parental obesity is associated with decreased mitochondrial functional capacity, as evidenced by lower intact cell respiration, oxidative phosphorylation and electron transport system capacity (159).

Effects of maternal obesity on breast milk composition and infant development

In addition to gamete-related influences, maternal obesity has been found to affect postnatal development through alterations in breast milk composition. Its normal composition includes macronutrients such as lactose, fats and proteins, as well as micronutrients, immune modulatory proteins (such as immunoglobulins and cytokines), growth factors, vitamins and a diverse microbiota (160). A mother's milk, as the primary source of micro- and macronutrients, as well as bioactive molecules, plays a central role in the early stages of infant development. A previous study examined the scientific evidence on how maternal obesity alters breast milk composition and its potential effects on infant growth and development (161).

As demonstrated in a previous study, maternal obesity appears to significantly alter the composition of breast milk, particularly the lipid profile. Obese women display increased breast milk fat and caloric content from foremilk to hindmilk, with the average milk caloric value being 11% greater (162). In addition, protein content also appears to be affected. Similarly, the same group of authors investigated the association between maternal BMI, serum lipids and insulin, as well as the fat and calorie content of breast milk, from foremilk to hindmilk (163). They concluded that, among all women, maternal serum triglycerides, insulin and the homeostatic model assessment for insulin resistance were significantly associated with the foremilk triglyceride concentration, suggesting that maternal serum triglyceride and insulin action contribute to human milk fat content. Maternal obesity significantly alters the hormonal composition of milk, as assessed by Enstad et al (164). The most significant alteration was observed in n-6:n-3 PUFA and leptin concentrations, which were later confirmed to be associated with accelerated weight gain in infancy (164). However, unlike the study by Enstad et al (164), a Chinese study found that the emaciated group had a significantly lower level of leptin in breast milk (165). Of note, correlation analysis showed that the level of ghrelin in breast milk was positively correlated with the Z score of current body weight (165). Another case-control study aimed to compare the levels of leptin, ghrelin, adiponectin and IGF-1 in pre-feed and post-feed breast milk from mothers with obesity and normal weight (166). The pre-feed breast milk of mothers with obesity had significantly higher levels of ghrelin than that of mothers with a normal weight. At the same time, adiponectin, an insulin-sensitizing hormone, appeared to be reduced in the post-fed milk of mothers with obesity compared to mothers with normal weight (166). Obesity appears to alter the expression of leptin, adiponectin, and miRNA, which typically decrease over time during lactation in normal-weight mothers (167). Additionally, miRNAs (miR-103, miR-17, miR-181a, miR-222, miR-let7c and miR-146b) are negatively associated with infant BMI only in normal-weight mothers (167).

Other components of human milk, named human milk oligosaccharides (HMOs), which serve as a source of energy for commensal intestinal microorganisms, have been studied in the context of obesity. These complex carbohydrates, unique to human milk, have been studied in a research project involving Mexican women (168). Specifically, six HMOs (LNFPI, 2'-FL, LNT, LNnT, 3'-SL and 6'-SL) were found to be significantly lower in overweight women compared to those of normal weight. One review article even mentions that maternal lifestyle affects the microbial composition of breast milk (169). Most notably, it appears that milk obtained from obese mothers contains lower microbial diversity, which may result in reduced amounts of Bifidobacteria in infants (169).

An overwhelming body of evidence suggests that maternal obesity, as well as other metabolic disorders such as diabetes, is the leading cause of divergent offspring development. However, paternal obesity has become a focus of research due to the emerging evidence of sperm-transmitted epigenetic changes that have a significant effect on offspring.

Current controversies and unresolved debates

Despite notable advances made in the understanding of the association between obesity and reproductive health, fundamental gaps and critical controversies remain that limit the ability of researchers to develop effective therapeutic interventions. A major ongoing challenge is to disentangle the direct effects of obesity itself from those attributable to dietary components, metabolic syndrome, and associated comorbidities. While a number of experimental models induce obesity using high-fat or high-sugar diets, the independent contributions of excess adiposity vs. specific nutritional factors on reproductive dysfunction have not yet been fully clarified. Molecular pathways, such as oxidative stress, chronic inflammation and epigenetic modifications potentially mediate these distinct influences; however, these require rigorous investigations using carefully controlled experimental designs that isolate obesity from dietary variables (Fig. 3).

Figure 3 Schematic illustration of the unresolved distinction between dietary components and obesity effects on reproductive mechanisms. On the left panel, major dietary components, including fat, sugar, protein, vitamins and supplementation, are shown as potential direct influencers on reproductive health. On the right panel, obesity-related factors, including adiposity, inflammation, and metabolic syndrome, are depicted as established contributors to reproductive dysfunction. However, it remains unclear which reproductive mechanisms are affected explicitly by dietary factors alone and which are driven by obesity itself, resulting in an unexplained mechanistic overlap. Therefore, distinct mechanisms of either diet or obesity on reproductive parameters such as gamete quality, hormonal imbalance, oxidative stress, and epigenetic effects remain to be elucidated. To distinguish the dietary impact from obesity's impact on reproduction, three approaches can be proposed: murine models of obesity caused by gene manipulation without dietary interventions (obesity's impact); short-term special diet feeding (impact of dietary components without causing obesity); long-term special diet feeding (obesity's impact). ST, short-term; LT, long-term; HFD, high-fat diet.

The direct effects of metabolism on gametes, fertilization and offspring health are incompletely understood. New evidence indicates that parental obesity alters DNA methylation, histone marks and non-coding RNA profiles in germ cells, potentially transmitting metabolic risks across generations. However, it remains controversial whether these epigenetic changes are causally linked to unfavorable reproductive outcomes or represent biomarkers for broader metabolic dysregulation. The relative contributions of maternal and paternal obesity to programming the development and disease susceptibility of offspring are also not yet clear.

The intrauterine microenvironment, a crucial factor for fetal development and long-term health, remains an under-researched, yet therapeutically promising area. A comprehensive characterization of the effects of obesity on uterine physiology, including pH, oxygenation, immune cell populations and molecular signaling networks is required. Cutting-edge technologies, such as single-cell RNA sequencing, spatial transcriptomics and metabolomics provide opportunities to map the molecular landscape of the obese reproductive tract with unprecedented resolution.

Another area of debate concerns the reversibility and treatment of obesity-induced reproductive impairments. Although preclinical studies have shown promise for antioxidant therapy, pharmacological agents and lifestyle interventions, including exercise and food modification, further research is required to confirm their effectiveness and durability across a range of human populations. Identifying precise molecular targets amenable to therapeutic modulation remains an urgent priority to translate mechanistic findings into clinical applications.

Key signaling pathways, including insulin/IGF signaling, AMPK, mTOR and inflammatory mediators, appear to be differentially regulated in obesity, affecting gametogenesis, steroidogenesis and embryo development. A more in-depthy understanding of their crosstalk, as well as the roles of epigenetic regulators and non-coding RNAs, will be critical for developing personalized interventions. To address these controversies and gaps, further research is required to integrate sophisticated molecular approaches with longitudinal cohort studies and experimentally rigorous models. Longitudinal tracking of metabolic and reproductive changes will clarify temporal relationships and causal mechanisms. Ultimately, this integrated effort is essential to improve diagnostic precision, guide the development of targeted interventions and optimize reproductive outcomes, thereby advancing clinical care and enhancing multigenerational health.

Conclusions

The present comprehensive review indicates that obesity exerts profound and multifaceted effects on reproductive health through complex molecular mechanisms that remain incompletely understood. While substantial progress has been made in documenting obesity-reproduction associations, the field now requires a fundamental shift toward mechanistic investigations that can guide therapeutic development.

The available evidence clearly demonstrates that obesity affects reproductive function through multiple pathways, including oxidative stress, chronic inflammation, hormonal disruption and epigenetic modifications. However, critical gaps remain in the understanding of the relative importance of these mechanisms, their temporal associations and their therapeutic targetability. The distinction between obesity-specific effects and those attributable to dietary factors or metabolic syndrome is a particularly important area that requires systematic investigation.

The identification of specific molecular pathways, such as mitochondrial dysfunction, inflammatory signaling and epigenetic modifications, provides a foundation for developing targeted interventions. However, the translation of these mechanistic insights into effective clinical therapies requires substantial additional research, including well-designed clinical trials with mechanistic endpoints.

Future research is warranted to prioritize mechanistic studies that can distinguish reversible from irreversible changes in obesity-induced reproductive dysfunction, identify specific therapeutic targets, and develop personalized interventions based on individual metabolic and reproductive profiles. Only through such systematic, mechanistic investigation can we hope to develop effective strategies for preventing and treating obesity-induced reproductive dysfunction.

The integration of advanced molecular techniques with carefully designed clinical studies offers unprecedented opportunities to understand and address the reproductive consequences of obesity. This represents both a scientific challenge and a clinical imperative, given the global prevalence of obesity and its impact on reproductive health across generations.

Availability of data and materials

Not applicable.

Authors' contributions

NP, MKr, MKu, KV and JB conceptualized the study. NP and MKr were involved in the literature search. NP, MKr, KV, DR and JB were involved in verifying the accuracy of the data extracted from the literature. NP, MKr, MKu, KV, DR and JB were involved in the writing and preparation of the original draft of the manuscript, and in the writing, reviewing and editing of the manuscript. NP and MKr were involved in the preparation of the figures. KV and JB supervised the study. JB was involved in project administration. All authors have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Abbreviations:

Acknowledgements

Not applicable.

Funding

No funding was received.

References