Obesity affects reproductive health by disrupting the HPO axis. Kiss1 neurons located in the hypothalamus, responsible for producing kisspeptin, are crucial in regulating the secretion of gonadotropin-releasing hormone (GnRH) and the release of gonadotropins. Kiss1 neurons function as metabolic sensors, linking energy balance to reproductive functions (Navarro, 2020). There are two distinct populations of kiss1 neurons, including those located in ARC (Kiss1^ARC) and those in anteroventral periventricular/periventricular nucleus (Kiss1^AVPV/PeN) of the hypothalamus. Ovarian steroids differentially regulate them. For instance, estradiol (E2) upregulates the production of kisspeptin in Kiss1^AVPV/PeN neurons while downregulating it in Kiss1^ARC neurons (Uenoyama et al., 2021). Additionally, Kiss1^ARC neurons co-express glutamate, while Kiss1^AVPV/PeN neurons co-express gamma-aminobutyric acid (GABA), with both neurotransmitters being upregulated by E2 in females. Furthermore, Kiss1^ARC neurons co-express receptors for leptin and insulin, and are activated by these hormones in a state of satiety. Kiss1^ARC neurons also stimulate anorexigenic POMC neurons while inhibiting orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, linking feeding behavior to reproductive functions (Navarro, 2020). Both Kiss1^ARC and Kiss1^AVPV/PeN neurons project to the paraventricular hypothalamic nucleus (PVH) neurons involved in satiety and the dorsomedial hypothalamus (DMH) neurons responsible for regulating energy expenditure, modulating their functions through the release of glutamate and GABA, with an upregulation by E2 in females (Figure 1; Rønnekleiv et al., 2022).

As a consequence of Kiss1 neuron dysfunction, obesity significantly affects GnRH-LH release patterns in females. Compared to women of normal weight, obese women exhibit significantly lower average LH levels when measured every 10 min over 12 h, with an exceedance of a 50% reduction in LH pulse amplitude during the follicular phase (Jain et al., 2007). This reduction results in inadequate corpus luteum formation and lower progesterone (P) production by the ovaries. Although obese women with lower follicular phase LH levels have similar serum E2 levels compared to non-obese women, obese women during ovulation exhibit a reduced LH surge, resulting in inadequate corpus luteum formation and lower mid-luteal P production (luteal phase deficiency) (Jain et al., 2007). While increased GnRH/LH pulse frequency is observed in obese individuals and those with PCOS, obesity primarily affects LH pulse amplitude rather than frequency, leading to an overall decrease in mean LH levels (Morales et al., 1996). In women with oligomenorrhea and anovulatory PCOS, both mean LH levels and LH pulse amplitude negatively correlate with BMI, further suggesting that obesity-induced metabolic changes contribute to reproductive endocrine dysfunction (Taylor et al., 1997).

In women with obesity, metabolic imbalances such as IR and increased adiposity alter the function of these hypothalamic neurons, leading to disrupted reproductive signaling. IR can impair hypothalamic insulin responsiveness, a phenomenon known as “brain IR” (Milstein and Ferris, 2021). Exposure to an HFD impairs ARC neurons, contributing to neuronal fibrosis, reduced insulin receptor activation in these hypothalamic neurons, and worsening brain IR (Beddows et al., 2024). Disruption of insulin signaling in neurons leads to reproductive dysfunction, such as reduced LH levels and infertility, as demonstrated by studies where InsR (insulin receptor) knockout in neural stem cells during early brain development is mediated by Nestin-Cre (Brüning et al., 2000). However, in models with widespread deletion of InsR in the brain, the pituitary’s responsiveness remains normal, indicating that the impact on LH levels may result from dysregulation of hypothalamic GnRH production rather than a direct pituitary defect (Brüning et al., 2000), thereby supporting the hypothesis that the hypothalamus is a key brain region for insulin’s action (Milstein and Ferris, 2021).

Insulin has been shown to affect reproductive function by directly modulating LH secretion. For example, injection of insulin into the lateral ventricle of insulin-deficient diabetic sheep and rats increases both the frequency and peak levels of LH pulses (Kovacs et al., 2002; Tanaka et al., 2000). However, insulin’s effects on GnRH production may be indirect, as conditional knockout of InsR in GnRH neurons does not affect puberty onset, estrous cycles, or litter size in female mice (Divall et al., 2010). This suggests that insulin may regulate reproductive function through other neural circuits. One such circuit involves kiss1 neurons, which are crucial for initiating the secretion of GnRH. Although only a subset of kiss1 neurons in female mice express InsR—approximately 22% in the ARC and 3%–5% in the periventricular region—insulin signaling in these neurons is critical for reproductive health (Qiu et al., 2013). Specific knockout of InsR in kiss1 neurons results in reduced LH levels and delayed puberty onset in female mice, although fertility and estrous cycles remain unaffected (Qiu et al., 2013). Interestingly, when IGF-1 receptors are also knocked out in kiss1 neurons, a reduction in litter size is observed, suggesting that insulin and IGF-1 signaling cooperate in these neurons to regulate reproductive function (Wang M. et al., 2024).

Interestingly, the crosstalk between IR and steroid hormone imbalance is also a key mechanism causing HPO axis dysfunction. In obese individuals, elevated insulin levels promote androgen production, which is then converted into additional estrogen by aromatase in adipocytes (Cirillo et al., 2008). Excess estrogen reduces LH production through negative feedback on the HPO axis, further impairing reproductive function. A study supporting this finding shows that aromatase inhibitors significantly increase LH pulse amplitude by 2.54-fold in obese women, a response not observed in women of normal weight (Venkatesh et al., 2022).

Leptin resistance (LR) is another characteristic feature of obesity, accompanied by elevated serum leptin levels (Izquierdo et al., 2019). The hypothalamus serves as the central target for leptin in regulating feeding, energy metabolism and reproductive functions. Although leptin overexpression accelerates puberty onset and enhances reproductive capacity in young female mice, prolonged hyperleptinemia eventually leads to hypothalamic hypogonadism characterized by prolonged estrous cycles, ovarian atrophy and impaired GnRH and LH secretion (Yura et al., 2000).

Leptin primarily exerts its effects through two types of neurons in the ARC of the hypothalamus: POMC and NPY/AgRP neurons. These neurons have opposing roles in regulating appetite and energy metabolism. POMC neurons release α-melanocyte-stimulating hormone (α-MSH), which acts on melanocortin receptors (MC3R and MC4R) in the hypothalamic preoptic area to produce anorexigenic effects. In contrast, NPY/AgRP neurons inhibit POMC activity by secreting AgRP, NPY, and GABA, counteracting the anorexigenic effect of POMC (Cowley et al., 2001; Schwartz et al., 1996; Stephens et al., 1995). Both POMC and NPY/AgRP neurons are interconnected with kisspeptin neurons, establishing a neurobiological link between metabolic regulation and reproduction. NPY/AgRP neurons inhibit kisspeptin neurons in the ARC and AVPV/PeN region of the hypothalamus, thereby reducing kisspeptin production and subsequently decreasing GnRH and LH secretion (Coutinho et al., 2020; Padilla et al., 2017). Conversely, POMC neurons activate Kiss1^ARC neurons, thereby promoting the release of GnRH and LH (Israel et al., 2012). Notably, kisspeptin and GnRH neurons either do not express LepR or express them at very low levels, suggesting that leptin likely influences the HPO axis predominantly through its effects on POMC and NPY/AgRP neurons (Louis et al., 2011; Figure 1). Experimental studies have shown that knockout of LepR specifically in AgRP neurons results in reduced LH production, arrested estrous cycles, and decreased fertility in female mice (Egan et al., 2017). These studies highlight the crucial role of NPY/AgRP neurons in mediating leptin’s impact on reproduction. Furthermore, hypothalamic nitric oxide (NO) neurons, which also express LepR, appear to play a role in leptin’s central regulation of the HPO axis. Approximately 20% of LepR-expressing neurons in the hypothalamus also produce NO via neuronal nitric oxide synthase (nNOS). Knockout of LepR in these NO neurons results in hyperphagic obesity, reduced energy expenditure, and hyperglycemia similar to what is observed in global LepR-deficient mice (Leshan et al., 2012).

On the other hand, NO, as a lipophilic gaseous molecule that senses leptin signals in the brain, can freely diffuse and act on neighboring neurons (such as GnRH neurons), regulating their pulsatile secretion activity. By knocking out the nNOS gene (nNOS^−/−) or pharmacologically inhibiting the activity of nNOS in the hypothalamic preoptic area, the promoting effect of exogenous leptin on LH secretion is significantly weakened, and leptin cannot restore the fertility of leptin-deficient female mice, proving that the nNOS/NO pathway is a necessary condition for leptin to regulate reproduction (Bellefontaine et al., 2014). Mechanistically, NO may directly activate the soluble guanylate cyclase (sGC)-cGMP pathway in GnRH neurons, modulating their excitability, or regulate the preoptic local neural circuitry (including Kisspeptin neurons or GABA/glutamatergic interneurons), indirectly controlling the GnRH pulse generator (Bellefontaine et al., 2014).

In summary, LR and excess leptin disrupt the functions of intermediate neurons, such as POMC, NPY/AgRP, and nNOS neurons. Through pathways including leptin-melanocortin-kisspeptin, leptin-NPY/AgRP-kisspeptin and leptin-nNOS/NO-kisspeptin, leptin influences both energy metabolism and GnRH release by modulating hypothalamic kisspeptin-producing neurons (Padilla et al., 2017; Leshan et al., 2012; Constantin et al., 2021; Hessler et al., 2020; Hill et al., 2010). Kisspeptin is thus considered a crucial link between leptin signaling and GnRH secretion, as well as a key integrator of metabolic energy homeostasis and reproductive function (Figure 1).

In individuals with obesity, inflammation is primarily driven by increased levels of inflammatory markers and activated signaling pathways, which contribute to systemic organ dysfunction (Cox et al., 2015). Obesity and prolonged HFD exposure result in chronic systemic inflammation, which significantly disrupts hypothalamic function and impairs reproductive endocrine function, indicating the hypothalamus is particularly vulnerable to obesity-induced inflammation (Sewaybricker et al., 2023). In the context of obesity, macrophages play a crucial role in driving systemic inflammation. These immune cells are abundant in adipose tissue, particularly visceral fat, and release inflammatory cytokines and other mediators that promote both peripheral and central inflammation (Weisberg et al., 2003). Although the blood-brain barrier (BBB) traditionally protects the brain from direct infiltration by peripheral immune cells, evidence suggests that macrophages from adipose tissue can infiltrate into the hypothalamus during obesity, thereby contributing to local inflammation (Valdearcos et al., 2017).

Despite the involvement of peripheral macrophages, resident central nervous system (CNS) immune cells, particularly microglia, appear to have a more prominent role in maintaining chronic hypothalamic inflammation. In obesity, hypothalamic microglia are activated by elevated circulating saturated fatty acids via the Toll-like receptor 4 (TLR-4)/NF-κB signaling pathway, leading to the polarization of microglia into a pro-inflammatory M1 macrophage-like phenotype, which exacerbates local inflammation in the hypothalamus (Lively and Schlichter, 2018). Recent studies have shown that depleting or inhibiting microglial activation can reduce BW, food intake, and peripheral macrophage infiltration, highlighting the close interaction between peripheral and central immune cells in sustaining hypothalamic inflammation (Valdearcos et al., 2017).

Astrocytes, another type of glial cell, also play a crucial role in hypothalamic inflammation. Under conditions such as autoimmune encephalopathy, brain injury, or microbial infections, astrocytes are activated and produce a range of inflammatory factors via the cytosolic phospholipase A2 (cPLA2)-NF-κB signaling pathway. Activated astrocytes release various inflammatory factors, including TNF, ILs, chemokine ligands, and colony-stimulating factors, which interact with microglia, oligodendrocytes, and neurons, influencing brain pathology and recovery (Linnerbauer et al., 2020). Disruption of NF-κB signaling in astrocytes has been shown to ameliorate HFD-induced hypothalamic inflammation, reduce weight gain, and improve glucose tolerance, highlighting the importance of astrocytic regulation in hypothalamic responses to obesity (Figure 2; Douglass et al., 2017).

Hypothalamic inflammation caused by obesity and HFD has profound consequences for reproductive health, which is commonly associated with menstrual irregularities and ovulatory dysfunction, such as those observed in PCOS (Barlampa et al., 2021). GnRH neurons express receptors for various inflammatory mediators, including interleukins, prostaglandins (PGEs), and TNF-α, suggesting that these neurons are directly regulated by inflammatory factors (Jasoni et al., 2005). For instance, IL-10 knockout results in impaired GnRH secretion and loss of estrous cycles (Barabás et al., 2018). In addition to these direct effects, inflammatory factors such as TNF-α and bacterial endotoxins, like lipopolysaccharide (LPS), can also indirectly influence kisspeptin neurons in the hypothalamus, thereby impairing GnRH secretion and further contributing to reproductive dysfunction (Lee et al., 2019; Sarchielli et al., 2017). The interplay between inflammation, kisspeptin neurons, and GnRH release highlights that inflammation can disrupt both the neural networks regulating reproductive hormone release and the feedback mechanisms necessary for normal reproductive function.

The ovaries are the primary organs responsible for producing oocytes and hormones, such as E2 and P, which are crucial to reproductive health. Ovarian function directly determines reproductive potential. Although the ovaries can still function to some extent in the absence of hypothalamic and pituitary function, obesity disrupts ovarian processes, directly impairing follicle development and oocyte quality. Oocyte meiosis is a critical process for oocyte maturation and successful fertilization. Oocytes are temporarily arrested at metaphase I of meiosis, during which the nuclear envelope remains intact, and are referred to as germinal vesicle (GV) stage oocytes. The resumption of meiosis involves the breakdown of the germinal vesicle (GVBD) and the first meiotic division, leading to spindle reorganization and ultimately, fertilization (Pan and Li, 2019). Spindle formation is critical for the completion of meiosis and oocyte maturation. In HFD-induced obese mice, oocytes exhibit reduced GVBD rates, abnormal spindle morphology, chromosome misalignment, and disrupted oocyte polarization, which contribute to increased rates of aneuploidy (Figure 2; Hou et al., 2016). Similarly, obese women undergoing IVF exhibit a higher incidence of spindle abnormalities and chromosomal misalignments in oocytes, leading to impaired oocyte maturation (Gonzalez et al., 2022; Machtinger et al., 2012). Furthermore, studies have shown that obesity alters gene expression in oocytes, upregulating CXCL2 and DUSP1, while downregulating TWIST1, ID3, GAS7, and TXNIP. These genes are involved in inflammation, oxidative stress, and lipid metabolism (Ruebel et al., 2017). These findings suggest that obesity impairs oocyte maturation and quality through both genetic and epigenetic alterations, including changes in DNA methylation and histone acetylation, which negatively affect chromatin stability during meiosis (Hou et al., 2016; Yun et al., 2019).

Mitochondria are crucial for oocyte quality, as they provide the energy needed for oocyte maturation, fertilization, and embryonic development (Bahety et al., 2024). Oocyte quality is closely associated with mitochondrial DNA (mtDNA) copy number and mitochondrial function. Primary oocytes exhibit substantial mtDNA expansion during early maturation, and oocytes with higher mtDNA copy numbers have a greater likelihood of fertilization success (Cao et al., 2007; Reynier et al., 2001). Additionally, Mitochondrial membrane potential and ATP production are also critical for oocyte quality (Figure 2; Acton et al., 2004). In obese female mice, oocytes exhibit mitochondrial dysfunction, including reduced mtDNA copy number, increased mtDNA mutations, impaired mitochondrial membrane potential, and elevated autophagy levels (Wu et al., 2015). Furthermore, oocytes from obese mice have diminished mitochondrial density, inhibited mitochondrial membrane potential, and accumulation of abnormal mitochondrial aggregates (Chen et al., 2024). Moreover, mature oocytes from obese mice show reduced mtDNA and increased mitochondrial single-nucleotide variant (mtSNV) rates, impairing mitochondrial energy function and oocyte quality (Chen et al., 2024). Obesity-induced damage to oocyte mitochondria may be related to the inhibition of AMPK activity, leading to increased binding affinity of the ATF5-POLG protein complex to the mutated mtDNA D-loop and protein-coding regions, thereby causing the replication of heteroplasmic mtDNA (Chen et al., 2024). Interestingly, mitochondrial damage in oocytes from obese mothers may also affect offspring, passing down metabolic and mitochondrial dysfunction across generations (Elías-López et al., 2023).

Granulosa cells, essential components of follicles, produce estrogen and play a vital role in oocyte differentiation and ovulation. In both individuals with obesity and PCOS, granulosa cells exhibit reduced proliferation, increased apoptosis, and impaired steroidogenesis, negatively affecting follicle maturation and oocyte quality (Nteeba et al., 2014; Peng et al., 2021). These abnormalities are often accompanied by elevated oxidative stress, mitochondrial dysfunction, decreased ATP levels, endoplasmic reticulum stress, and autophagy dysfunction in granulosa cells (Zhao et al., 2023). Obesity-induced lipotoxicity and metabolic dysfunction in granulosa cells contribute to these impairments, reducing female fertility (Hua et al., 2020). Additionally, certain non-coding RNAs, such as miR-133a, play a role in obesity-induced granulosa cell apoptosis, targeting typical anti-apoptotic genes, including C1QL1 and XIAP, and pro-apoptotic genes, such as PTEN (Chen et al., 2023). Studies have also revealed that obesity affects granulosa cells at various stages of follicle development. For example, in obese mice, excessive proliferation of granulosa cells in primordial follicles accelerates follicular depletion, mimicking PCOS-like ovarian phenotypes and reducing ovarian reserve (Zhou et al., 2023). This study employed laser capture microdissection and RNA sequencing to dissect and analyze primordial and primary follicles at various developmental stages, aiming to identify gene expression changes during the transition from primordial to primary follicles (PFT). The results showed significant increases in ferroptosis, oxidative stress, vascular endothelial growth factor, and mTOR signaling markers in primordial follicles from obese mice, suggesting that increased lipid metabolism-related ferroptosis in obesity may be a key mechanism for excessive activation of primordial follicles (Zhou et al., 2023). Recent single-cell sequencing (scRNA-seq) studies have found that in both diet-induced and leptin-deficient obese mice, the granulosa cell subtype expressing inhibin B increases, and pseudo-temporal analysis has shown that this granulosa cell subtype is mainly distributed in more mature antral follicles. Moreover, obesity induces a shift in granulosa cell subtypes, contributing to follicular arrest and impaired follicle maturation, which is further influenced by altered androgen production by theca cells in obese ovaries (Long et al., 2022; Salilew-Wondim et al., 2015).

The ovarian microenvironment (OME), comprising follicular fluid, stroma, vasculature, and immune cells, plays a crucial role in regulating ovarian functions, including follicular development, hormone production, and oocyte maturation (Duffy et al., 2019; Shen et al., 2023). Chronic low-grade inflammation in the ovarian microenvironment is a key factor contributing to follicular dysfunction in obesity. Elevated levels of pro-inflammatory cytokines (e.g., TNFα, IL-6, IL-8) and oxidative stress markers in the ovaries of obese individuals disrupt normal ovarian function and accelerate ovarian aging (Snider and Wood, 2019; Xiong et al., 2011). The excessive pro-inflammatory factors (IL-1, IL-6, TNFα, and CRP) and oxidative stress factors (H2O2, oxLDL) in the ovarian tissue and follicular fluid of obese individuals may be produced by follicular cells and immune cells within the ovary (Ruebel et al., 2017; Nteeba et al., 2014) or be associated with elevated circulating inflammatory factors in obese individuals (Figure 3). Therefore, systemic inflammation in obese individuals can be transmitted to the ovaries and even the follicular fluid, thereby affecting ovarian function.

Obesity also leads to dysregulation of ovarian angiogenesis, which is essential for supplying nutrients and oxygen to developing follicles. During early development, small follicles lack their own vascular network and rely on stromal vessels for nutrients and oxygen. As follicles mature, each creates its own vascular network within the theca layer, ensuring an independent supply of nutrients and oxygen separate from other follicles. Alterations in angiogenesis can lead to the formation of abnormal vascular structures, which can negatively impact follicle development and ovulation (Duncan and Nio-Kobayashi, 2013). In addition to chronic inflammation, dysregulation of angiogenesis has also been observed in the ovaries of obese and PCOS individuals (Di Pietro et al., 2018). For example, increased neovascularization and an imbalance of pro/antiangiogenic factors are present in the ovarian stroma of PCOS, and this dysregulation of angiogenesis is thought to contribute to the characteristic ovarian features of PCOS, such as abnormal follicular development, increased numbers of small follicles, failure of dominant follicle selection, anovulation, and the formation of follicular cysts (Di Pietro et al., 2018). Angiogenic factors, such as vascular endothelial growth factor (VEGF), not only stimulate vascular formation but also directly affect theca cells or granulosa cells, influencing follicular development and their endocrine function (Irusta et al., 2010). In high-fat and fructose diet-induced obese mice, early ovarian follicle accumulation and reduced numbers of mature follicles and corpora lutea are accompanied by a decrease in the number of microvessels in early follicles. This phenotype may be related to the excessive expression of IL-10 in the periovarian adipose tissue during obesity, which disrupts the function of VEGF and contributes to ovarian aging. This effect can be mitigated by treatments such as metformin (Yang et al., 2021). Recent single-cell and spatial transcriptomic sequencing studies have provided high-resolution cellular maps of the impact of obesity on the ovarian microenvironment. The study found that genetic obesity of OB/OB mice, but not HFD-induced obesity, significantly altered the proportions of granulosa cells, theca-stroma cells, luteal cells, and vascular endothelial cells in the ovary. Obesity severely disrupted granulosa cell differentiation from small to large follicles. Functionally, HFD enhanced FSH sensitivity and related hormone production, whereas OB/OB mice had decreased FSH sensitivity, insufficient steroid hormone production, and impaired follicular development. These differences can be attributed to the distinct expression patterns of the transcription factor Foxo1 in the two types of obese mice (Jiang et al., 2024).

In animal experiments, the effects of obesity on ovarian reserve function have shown variability. In diet-induced obesity (e.g., high-fat and high-carbohydrate diets) in rodents, rapid depletion of ovarian reserves has been observed (Wang et al., 2014). Similar findings have been reported in rabbit studies (Díaz-Hernández et al., 2022). Conversely, caloric restriction or maintaining optimal nutrition can reduce primordial follicle activation, increase the number of quiescent primordial follicles, prolong reproductive lifespan, and delay the onset of menopause (Garcia et al., 2019). Compared to caloric-restricted rats, diet-induced obese rats exhibit mTOR-related signaling associated with aging, along with decreased expression of anti-aging molecules such as SIRT1, SIRT6, FOXO3a, and NRF-1 (Wang et al., 2014). Enhanced mTOR signaling is also associated with the overactivation and depletion of primordial follicles, suggesting that obesity may accelerate ovarian reserve depletion by excessively activating mTOR pathways (Guo and Yu, 2019). These findings align with the conclusions drawn from studies using laser capture microdissection and RNA sequencing to investigate the characteristics of the primordial to primary follicle transition in obese mice, which suggest that obesity may accelerate primordial follicle pool depletion and decline in ovarian reserve function through excessive activation of mTOR signaling (Zhou et al., 2023). In OB/OB mice, despite increased follicular atresia, reduced numbers of pre-ovulatory follicles (large antral follicles), and a significant decrease in the number of corpora lutea, the expression of markers related to ovarian reserve, including Dazl, Stra8, and ZP3 mRNA, are increased. Additionally, the count of primordial follicles is also elevated, suggesting that leptin deficiency may have a protective effect on ovarian reserve under certain genetic conditions (Mollah et al., 2021). The differences in the effects between diet-induced and genetic obesity on ovarian reserve may be influenced by leptin, as diet-induced obesity is often accompanied by elevated circulating leptin levels, which may accelerate follicular overactivation through stimulation of the HPO axis. Elevated leptin might also directly affect granulosa cells by inhibiting anti-Müllerian hormone (AMH) expression, contributing to excessive follicle depletion (Merhi et al., 2013).

In addition to reduced ovarian reserve, increased extracellular matrix deposition, fibrosis, and the accumulation of senescent cells are also hallmarks of ovarian aging. These changes are also commonly observed in PCOS (Zhou et al., 2017). Chronic low-grade inflammation in the ovary is believed to contribute to these ovarian aging phenotypes (Isola et al., 2024). Increased ovarian fibrosis and the accumulation of senescent cells have been observed in HFD-induced obese rats and OB/OB mice, characterized by increased expression of p21 and p16, increased lipofuscin staining, and macrophage infiltration (Kawai et al., 2021). Additionally, ovarian fibrosis phenotypes similar to those observed in age-dependent ovarian aging have been reported in genetic obesity mice with Alms1 gene mutations (Umehara et al., 2022). Macrophages may play an important role in mediating inflammation-induced ovarian fibrosis and aging. The pro-inflammatory M1 macrophage phenotype is predominant in obese and PCOS ovaries (Feng et al., 2023) and promotes granulosa cell apoptosis and follicular atresia through the production of cytokines such as TNF-α, IL-1α/β, IL-6, and IL-18, thereby promoting the high expression of inflammasome genes such as NLRP3 and apoptosis associated speck like protein containing caspase activation and recruitment domain (ASC). During the later stages of reproductive age, increased extracellular matrix and fibrosis may also be linked to the M2 macrophage subtype, which produces factors such as TGF-β, FGF, and PDGF, as well as pro-inflammatory cytokines like IL-6, that contribute to fibrosis (Vasse et al., 2021).

Besides, both obesity and aging can induce similar pathological changes in the ovarian microenvironment, such as mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, liptoxicity and inflammation (Wu et al., 2015; Snider and Wood, 2019; Tatone et al., 2008). The anti-fibrotic drug BGP-15 can reverse obesity- and aging-induced ovarian fibrosis by inhibiting M2 macrophage polarization and MMP13 protein upregulation, as well as correcting mitochondrial dysfunction, oxidative damage, and ER stress in the ovarian stroma (Umehara et al., 2022). Interestingly, metformin, a typical anti-inflammatory and anti-aging drug, has also been found to prevent age-dependent ovarian aging in mice by altering the functional subpopulations of macrophages and fibroblasts in the ovary, and it can also reverse premature ovarian fibrosis in obese mice (Umehara et al., 2022; Landry et al., 2022).

PCOS is a common reproductive endocrine-metabolic disease among adolescent and reproductive-age women, which is characterized by infrequent ovulation, menstrual disorders, and HA, and is commonly associated with obesity, IR, and HA. The coexistence of these phenotypes in PCOS can be understood as an adaptive response to adverse environments such as resource scarcity. Elevated androgen levels, in particular, may represent an evolutionary adaptation that enabled females to engage in survival activities, such as hunting or defending against predators, by enhancing energy mobilization and physical resilience (Parker et al., 2022). Additionally, IR can also be present in individuals with PCOS who have a normal BW (Diamanti-Kandarakis and Dunaif, 2012). In women with PCOS, IR and hyperinsulinemia are key contributors to elevated androgen levels through multiple mechanisms: a) Insulin inhibits hepatic production of sex hormone-binding globulin (SHBG), leading to increased circulating free testosterone levels (Preziosi et al., 1993); b) Insulin acts directly on the InsR in theca cells or enhance the effect of IGF-1 on theca cells by reducing insulin-like growth factor-binding proteins (IGFBPs), thereby increasing LH-dependent ovarian androgen production (Franks and Hardy, 2018); c) Insulin can centrally stimulate the pituitary to secrete more LH, further promoting excessive androgen production by theca cells and ovarian stromal cells (Figure 3).

In a physiological context, androgens play a crucial role in female reproductive health, bone integrity, and cognitive function (Bianchi et al., 2021). However, excessive androgen levels in women can result in systemic damage. HA promotes the differentiation of preadipocytes into mature adipocytes, resulting in adipocyte hypertrophy and central obesity. This exacerbates dyslipidemia, oxidative stress, and systemic inflammation, which in turn worsen both obesity and IR (Lonardo et al., 2024). The systemic effects of elevated androgens are linked to an increased risk of CVD, NAFLD, T2DM, and malignancies in PCOS patients (Ye et al., 2021). Moreover, excessive androgen exposure in utero can predispose female offspring to obesity, PCOS, and other metabolic disorders in adulthood (Abbott et al., 1998; Nohara et al., 2013; Padmanabhan et al., 2010; Recabarren et al., 2005). Additionally, elevated androgens also disrupt the HPO axis, impairing ovulation and reproductive function. Although androgen receptor (AR) expression is higher in the male brain compared to the female brain, ARs are also present in the hypothalamus and extrahypothalamic nuclei of females, including fetal female mice (Handa et al., 1986). Under hyperandrogenic conditions, AR activation in the hypothalamus may induce inflammation (Ubba et al., 2023) and alter the firing frequency of GnRH neurons, thereby affecting their pulsatile release through GABA signaling, which likely increases LH pulse frequency not via kisspeptin pathways (Moore et al., 2015). At the pituitary level, AR activation enhances the pituitary’s sensitivity to GnRH, particularly increasing LH secretion, leading to the characteristic elevated LH/FSH ratio seen in PCOS (Schanbacher et al., 1987). At the ovarian level, excess androgens suppress granulosa cell proliferation through mechanisms such as upregulating phosphatase and tensin homolog (PTEN) expression, which is PPARγ-dependent, or by disrupting WNT signaling, both of which lead to follicular arrest and polycystic ovary formation (Chen et al., 2015; McFee et al., 2021). Additionally, androgens regulate granulosa cell apoptosis through inflammatory pathways, promoting inflammasome expression and pyroptosis (Wang et al., 2020). Androgens can also inhibit granulosa cell proliferation by suppressing interferon-gamma (IFN-γ) expression, thereby contributing to ovarian dysfunction in PCOS (Li Y. et al., 2019; Figure 3). Interestingly, studies suggest that neuron-specific AR signaling may play a more critical role in the development of PCOS phenotypes than peripheral AR (Caldwell et al., 2017). For instance, mice with neuron-specific AR deletion (NeuARKO) are resistant to developing the PCOS phenotype induced by dihydrotestosterone (DHT) (Caldwell et al., 2017). In contrast, global AR knockout mice (ARKO) treated with testosterone exhibit normal estrous cycles and corpus luteum formation, suggesting that the action of testosterone may primarily occur in non-ovarian tissues, which is the key site for the androgenic action that produces the PCOS phenotype (Caldwell et al., 2017).